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Frigerio, S. Role of the Immune System in IBD-Associated Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/16945 (accessed on 30 July 2024).
Frigerio S. Role of the Immune System in IBD-Associated Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/16945. Accessed July 30, 2024.
Frigerio, Sofía. "Role of the Immune System in IBD-Associated Cancer" Encyclopedia, https://encyclopedia.pub/entry/16945 (accessed July 30, 2024).
Frigerio, S. (2021, December 09). Role of the Immune System in IBD-Associated Cancer. In Encyclopedia. https://encyclopedia.pub/entry/16945
Frigerio, Sofía. "Role of the Immune System in IBD-Associated Cancer." Encyclopedia. Web. 09 December, 2021.
Role of the Immune System in IBD-Associated Cancer
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This entry is adapted from the peer-reviewed paper 10.3390/ijms222312739

Patients with inflammatory bowel disease (IBD) have increased incidence of colorectal cancer (CRC). IBD-associated cancer follows a well-characterized sequence of intestinal epithelial changes, in which genetic mutations and molecular aberrations play a key role. IBD-associated cancer develops against a background of chronic inflammation and pro-inflammatory immune cells, and their products contribute to cancer development and progression. In recent years, the effect of the immunosuppressive microenvironment in cancer development and progression has gained more attention, mainly because of the unprecedented anti-tumor effects of immune checkpoint inhibitors in selected groups of patients. Even though IBD-associated cancer develops in the background of chronic inflammation which is associated with activation of endogenous anti-inflammatory or suppressive mechanisms, the potential role of an immunosuppressive microenvironment in these cancers is largely unknown.

IBD IBD-associated cancer inflammation immune system immune cells immunosurveillance immunosuppression colitis-associated cancer colorectal cancer

1. Introduction

Ulcerative Colitis (UC) and Crohn’s Disease (CD) are the two forms of inflammatory bowel disease (IBD), characterized by chronic inflammation of the digestive tract leading to diarrhea, rectal bleeding and abdominal pain. One of the most severe complications of IBD is the development of colorectal cancer (CRC). It is generally accepted that the continuous exposure of intestinal epithelial cells (IECs) to proinflammatory stimuli and excessive cell damage with increased IECs turnover results in both genetic and immunological alterations, making IBD patients prone to developing CRC [1][2][3]. Population-based evaluations estimate that UC increases the risk of developing CRC two to three-fold compared to the non-IBD population [4][5] and patients with CD have also been reported to have increased CRC risk when compared to the general population [6][7]. The risk of developing CRC increases significantly after 10 years of IBD diagnosis and is higher in patients with continuous chronic intestinal inflammation, highlighting the crucial role of a prolonged inflamed environment in the pathogenesis of IBD-associated cancer [8][9][10]. Compared to sporadic CRC, IBD-associated cancer has worse overall survival rates. The reported differences in clinical features, disease pathogenesis and epidemiologic characteristics, which may be explained by differences in tumor biology, have recently been excellently reviewed [11].

IBD-associated tumorigenesis follows a multistep sequence of genetic and morphological alterations in the intestinal epithelium, from inflamed intestinal mucosa to dysplasia and finally carcinoma [12][13]. The genetic mutations that drive the progression from dysplasia to carcinoma in IBD-associated cancer have been extensively studied and include mutations in tumor suppressor genes (TP53 mutations) and in genes that regulate the cell cycle and cell proliferation such as KRAS and APC mutations. Surprisingly, there is very little difference in the genetic mutations that drive carcinogenesis among IBD-associated cancer and sporadic CRC [14][15].

As IBD-associated dysplasia develops in the background of chronic inflammation, studies have highlighted the role of pro-inflammatory cytokines on tumorigenesis. Most observations were made in mouse models [16][17][18][19]. Little is known about the potential role of endogenous anti-inflammatory or immunosuppressive mechanisms that evolve as a consequence of chronic inflammation in the gastrointestinal tract, although such immunosuppressive mechanisms may contribute to tumorigenesis by impairing anti-tumor immunity.

2. The Role of the Immune System in IBD-associated Cancer

2.1 Immune Signaling Pathways in IBD: Contribution to Cancer Onset

2.1.1 NF-κB/TNF-α

NF-κB is a family of transcription factors which play a role in inflammation, cell proliferation and malignant transformation [20]. In both canonical and non-canonical pathways, NF-κB forms a complex with its inhibitor IκB in the cytoplasm. In response to diverse stimuli such as inflammatory cytokines, growth factors or microbial components, IκB is degraded by IκB kinase (IKK complex) and NF-κB is translocated into the cell nucleus as part of the canonical pathway [21]. Once in the nucleus, it regulates the transcription of pro-inflammatory cytokines, chemokines and other inflammatory mediators that will promote and sustain the inflammatory reaction. As a pivotal regulator of the inflammatory responses, NF-κB has been implicated in the pathogenesis of IBD [22] . Furthermore, it has been shown that NF-κB contributes to IBD-associated tumorigenesis, mainly by activating the transcription of pro-inflammatory cytokines and by promoting tumor growth and metastasis via promotion of angiogenesis-related genes and anti-apoptotic genes[23][24] (Figure 1). The crucial role of NF-κB in IBD-associated cancer development has been demonstrated in vivo in a mouse colitis-associated cancer (CAC) model; Azoxymethane (AOM)/dextran sulfate sodium (DSS) model, in which inactivation of the canonical NF-kB signaling pathway through specific ablation of NF-κB kinase B (IKKβ) in intestinal epithelial cells reduced tumor incidence. Interestingly, deletion of the gene encoding IKKβ in myeloid cells decreased both tumor number and size, demonstrating the importance of NF-κB signaling in immune cells in CAC development [25]. In another study in AOM/DSS-treated mice, deletion of NLRP12, a member of the Nod-like receptor family which negatively regulates NF-κB, resulted in severe colitis and increased susceptibility to CAC as compared to wild-type mice[26]. This further demonstrates the important pro-tumorigenic role of NF-κB in IBD and IBD-associated cancer by limiting apoptosis and by promoting the production of pro-inflammatory cytokines.
Ijms 22 12739 g003 550
Figure 1. Pro-inflammatory immune signaling pathways in IBD and their contribution to IBD-associated cancer. Disruption of the intestinal epithelial layer causes the entry of luminal microorganisms. Pathogen-specific structures are recognized in the intestinal mucosa via Toll-like receptors by innate immune cells, activating the transcription factor NF-κB and promoting TNF-α, IL-6 and IL-1β production. NF-κB also stimulates transcription of vascular endothelial growth factor and a number of anti-apoptotic genes, enhancing angiogenesis, cell survival and proliferation. IL-6 has a potent pro-tumorigenic effect, mainly via STAT3 signaling. It binds to soluble or membrane-bound receptors which interact with gp130 either in intestinal epithelial cells or immune cells, triggering the activation of signaling molecules and transcription factors, including STAT3. STAT3 regulates the transcription of genes related to cell proliferation and survival and stimulates activation of NF-κB, creating a positive feedback loop. It also stimulates production of IL-22 by CD4+ T cells, which is important in intestinal homeostasis but potentially also facilitates carcinogenesis. Microbial recognition by antigen presenting cells also stimulates production of IL-23 via STAT3 signaling, leading to Th17 polarization with the subsequent production if IL-17A, IL-17F and IL-22, cytokines associated with carcinogenesis. (TLRs: toll-like receptor, VEGF: vascular endothelial growth factor).
Moreover, NF-κB is a transcription factor for many pro-inflammatory cytokines, such as TNF-α, a pleiotropic cytokine that promotes IECs apoptosis and acts on innate immune cells via activation of the NF-κB transcription pathway, among other important functions[27][28]. TNF-α seems to play a controversial role in cancer progression in IBD. It can induce epigenetic changes and can promote oncogene expression levels[29]. The pro-tumorigenic role of TNF-α in the progression to cancer under chronic inflammatory conditions was demonstrated in CAC mouse models, in which treatment with anti-TNF-α antibodies decreased both inflammation and the number of intestinal carcinomas [16]. Furthermore, administration of a transmembrane TNF-α antibody in an AOM/DSS mouse model dampened the inflammatory response and tumor formation. Anti-tumorigenic effects were observed both during the inflammation induction cycles with DSS and after CAC development, highlighting transmembrane TNF-α as a candidate target for treatment[30]. Unfortunately, there are currently no human data available that demonstrate a clear effect of anti-TNF antibodies in protection from IBD-associated cancer [31]. However, two cohort studies with long-term follow-up of IBD patients treated with the anti-TNF-α antibody infliximab, did not show increased CRC incidence[32][33].

2.1.2 IL-6/STAT3 and IL-22/STAT3

IL-6 is produced by innate immune cells residing in the intestinal mucosa and regulates survival and proliferation of IECs[34]. Importantly, IL-6 has been demonstrated to have a strong impact on the early progression to carcinoma in IBD via STAT3 signaling (Figure 1). Increased expression of IL-6 and STAT3 was demonstrated in biopsies from UC patients with active disease and in IBD-associated carcinomas, as compared to patients with inactive disease or controls [35] . In CAC mouse models, IL-6 ablation reduced tumor formation and mice injected with recombinant IL-6 had increased tumor load. This was STAT3-dependent, as deletion of STAT3 specifically in IECs resulted in lower tumor numbers and size, as well as a reduced percentage of proliferating cells in colonic crypts[36]. Further research into the possible mechanism of IL-6-mediated tumor promotion showed that macrophage-derived IL-6 attached to a soluble IL-6R is crucial in IL-6 trans-signaling in intestinal epithelial cells and thus in the development of CAC [20]. Thus, several studies have shown that IL-6, and downstream STAT3 signaling, is a critical tumor-promoting cytokine in CAC.
STAT3 may also be indirectly involved in CAC via activation of IL-22 production, for example by CD4+ T cells [37]. IL-22 is an important cytokine for epithelial cell and mucus layer regeneration, as well as for the production of antimicrobial compounds and mucosal wound healing [38][39] (Figure 1). However, despite its role in intestinal homeostasis, IL-22 may also possess pro-tumorigenic effects, as increased expression of IL-22, IL-22R and phosphorylated STAT3 have been demonstrated in inflamed and dysplastic intestinal tissues from UC patients [40][41].

2.1.3 NFAT

NFAT is a family of transcription factors mainly expressed in T cells, which regulate important activating signaling pathways. NFAT has been shown to be involved in both IBD pathogenesis and CRC development [42][43][44]  and has therefore also been studied in CAC development. In a CAC mouse model, NFATc2-deficiency resulted in decreased tumorigenesis, which was accompanied by reduced intestinal inflammation and decreased production of the pro-inflammatory cytokines IL-6 and IL-21 by CD4+ T cells in spleen and lamina propria. Furthermore, the administration of hyper IL-6 abrogated the effect of protection in NFATc2-KO mice [45]. This shows that NFATc2 promotes tumorigenesis in the context of colitis, in a process dependent on IL-6. Apart from NFATc-2, NFATc-3 has been shown to be upregulated in AOM/DSS-treated CAC mice as compared to control mice. Mice deficient in NFATc3 showed a decrease in tumor numbers and size. In addition, NFATc3 inhibited proliferation and epithelial to mesenchymal transition in vitro in a CRC cell line [46]. In conclusion, NFATc2 and NFATc3 are key regulators of intestinal inflammation and are important in the initiation and progression of IBD-associated cancer.

2.1.4 IL23/STAT3/Th17 Signaling Pathway

IL-23 is produced by a variety of immune cells, including antigen presenting cells (APCs), and plays an important role in sustaining the inflammatory response in IBD [47][48]. The IL-23 heterodimer is made up of the p19 and the p40 subunit. Once IL-23 binds to its receptor IL-23R, it activates janus kinases, which will then phosphorylate the receptor, inducing the recruitment of several STAT proteins, including STAT3. Ultimately, IL-23 signaling activates the transcription of effector cytokines genes belonging to the Th17 subtype, such as IL-17A, IL-17F, IL-22 and IFN-γ [49] (Figure 1). The role of the IL23/Th17 pathway in CAC pathogenesis is not completely clear, but IL-17A appears to drive tumor formation in mouse models for inflammation-induced cancer, as both a blockade of IL-17A by anti-IL-17A antibodies [50], and genetic deletion of IL-17A [51]  was associated with decreased tumor size and number.
According to the pro-tumorigenic role of the IL-23/Th17 signaling pathway, it could be envisioned that treating IBD patients with anti-IL-23 or anti-IL-17A antibodies would also contribute to a decrease in CAC incidence, both indirectly by decreasing inflammation, but potentially also directly. Ustekinumab, a humanized monoclonal antibody that binds to the p40 subunit, is currently used for the treatment of UC [52] . Even though clinical data are still lacking, preliminary results in a mouse preclinical model identified IL-23 as a promising target to prevent CRC associated with chronic inflammation in IBD [53]. One of the important effects of the use of ustekinumab that needs to be considered as a risk factor for CRC is that blocking p40 is also associated with decreased levels of anti-tumorigenic IL-12 [54][55]. Fortunately, randomized clinical trials reported very low incidence of colorectal cancer patients receiving Ustekinumab as compared to patients receiving placebo, even though the follow-up period was short (52 weeks) [56], and long-term safety data for its use in UC patients will follow.

2.2 Immune cells in IBD and Its Contribution to IBD-Associated Cancer

2.2.1 Macrophages

Macrophages, mainly tissue-resident cells belonging to the innate immune system, are involved in both anti-inflammatory (M2 or alternatively activated) as well as pro-inflammatory (M1 or classically activated) immune responses. In the intestine, monocytes change into tolerogenic lamina propria macrophages, which are hyporesponsive to microbial stimuli and do not initiate inflammatory responses[56] . In addition, these macrophages produce large amounts of anti-inflammatory cytokines, such as IL-10 and TGF-β, creating a tolerogenic environment and promoting the expansion of CD4+CD25+ Treg T cells[57] . Biopsies from IBD patients demonstrate a high abundance of monocyte-derived macrophages infiltrating the intestinal mucosa, predominantly of the M1 or pro-inflammatory phenotype[58][59][60]. More recently, it was shown that the non-dysplastic mucosa from IBD patients is populated by both M1 and M2 macrophages [61] .
Classically, M1 macrophages participate in anti-tumor immunosurveillance by directly acting as APCs to activate T cells. In addition, macrophages produce cytokines that determine polarization to different effector T-cell subtypes and phagocytose neoplastic cells that are covered with antibodies and other opsonins [62]. In IBD, macrophages have also been proposed to actively play a role in tumorigenesis. M1 proinflammatory macrophages foster a pro tumorigenic environment by producing tumor-promoting cytokines, which exert a well-known proliferative effect on colonic cells via induction of transcription factor NF-κB and signal transducer STAT3 [63][64] . Macrophages have also been identified in IBD-associated dysplastic lesions and the level of macrophage infiltration correlated positively with the number of dysplastic lesions [65] . In line with these results, Khan and colleagues also identified a progressive increase in macrophage density from colitis to dysplasia and cancer [66]. Although the phenotype of these macrophages was not identified, another study showed that the percentage of M2-like macrophages markedly increased in IBD-associated cancers, suggesting a polarization to anti-inflammatory or immunosuppressive macrophages in the transition from dysplasia to carcinoma [67]. In support of this, Kvorjak et al. showed that CD163+ M2-like macrophages are significantly increased in intestinal tissue from UC- and IBD-associated cancer patients [68] . Moreover, the authors postulate that CCL17 and IL-13 produced by these CD163+ M2 macrophages induce activation of oncogenic pathways involving AKT and STAT6, as well as expression of aberrant glycans on colonic epithelial cells which inhibit activity of DCs and NK cells, thus dampening immunosurveillance (Table 1). Another intriguing anti-inflammatory mechanism by which macrophages may promote tumorigenesis is by the abolishment of T cell proliferation through nitric oxide production. More specifically, it was shown that macrophages that express inducible nitric oxide synthase (iNOS) were capable of suppressing antigen-specific T-cell responses against Listeria monocytogenes in the spleen[69]  (Table 1). As iNOS+ macrophages are abundant in inflamed intestinal mucosa in IBD, it seems plausible that they also exert a suppressive effect in T cells, affecting immunosurveillance against the malignant transformed cells that appear in the pro-tumorigenic, inflamed milieu. It has also been proposed that macrophages may have a dichotomous effect in IBD-associated cancer via TGF-β activation by the nuclear receptor PPAR-γ. In particular, linoleic acid, a chemical compound present in the diet, activates PPAR-γ, which stimulates macrophages to produce TGF-β, ameliorating colitis symptoms but increasing tumorigenesis in a CAC mouse model [70] .
Table 1. Possible anti-inflammatory and immunosuppressive mechanisms that may dampen immunosurveillance during IBD-associated carcinogenesis.
Immune Cell Mechanism
Macrophages
−
Accumulation of CD163+ M2 macrophages that activate oncogenic pathways via IL-13 and CCL17 in UC and CAC patients [68]. 
−
Glycan-induced expression on colonic epithelial cells by CD163+ M2 macrophages that inhibit NK and DC function in UC and CAC patients [68].
−
Inhibition of T-cell responses via iNOS+ macrophages [69].
−
TGF-β production by PPAR-γ expressing macrophages [70].
Dendritic
Cells (DCs)
−
Notch-2- DCs with less migration to MLNs and antigen presentation capacity to CD8+ T cells [71] .
−
Plasmacytoid dendritic cells (pDCs) induce recruitment of MDSCs into intestinal mucosa in a CAC mouse model [72] .
Myeloid-derived suppressor cells (MDSCs)
−
CXCR2-expressing MDSCs in mice colonic mucosa inhibit CD8+ T effector functions [73] .
T cells
−
Increased expression of inhibitory markers (PD-1, CTLA-4, PD-L1) in CD8+ T cells in IBD-associated cancer tumors and intestinal epithelium from CAC mice [74][75] .
−
Decreased granzyme B expression in CD8+ T cells in IBD-associated cancer patients [76] .
−
Tregs suppress CD8+IFN-γ+ T cells producers of granzyme B in a CAC mouse model [77][78].
Natural Killer (NK) cells
−
Limited killing capacity and mitochondrial activity of circulating NK cells from IBD patients [79] .
In conclusion, macrophages display both pro- and anti-inflammatory mechanisms that contribute to IBD-associated cancer. It could be envisioned that M1 macrophages initially invade IBD-inflamed mucosa and are involved in carcinogenesis by the production of pro-inflammatory mediators. M1-like macrophages acquire a more M2-like immunosuppressive phenotype as inflammation becomes chronic, and indeed a higher abundance of M2 macrophages with anti-inflammatory properties is observed in dysplastic lesions and carcinomas in IBD. This could further accelerate carcinogenesis as their immunosuppressive phenotype hinders adequate immunosurveillance. To better characterize these mechanisms, more studies into the role of macrophages in IBD-associated cancer are necessary.

2.2.2 Neutrophils and Eosinophils

Apart from monocyte-derived macrophages, other polymorphonuclear cells such as neutrophils and eosinophils are recruited into the inflamed mucosa in IBD [80][81], but their role in promoting IBD-associated cancer has not yet been well addressed. Interestingly, expression of the transcription factor BATF3 in intestinal epithelial cells promoted the transcription of CXCL5, which together with CXC chemokine receptor (CXCR)- 2 stimulate neutrophil recruitment, which was associated with increased CAC development in AOM/DSS-treated mice [82]. Neutrophils have a prominent place in IBD pathophysiology, being a central effector cell in inducing mucosal damage, producing reactive oxygen species, reactive nitrogen species and other specific enzymes that disrupt intestinal tissue [83]. This can also promote dysplasia and carcinoma development in the context of IBD, as neutrophil-derived products generate DNA damage and genetic mutations and result in increased epithelial cell proliferation [84]. Conversely, some studies show that neutrophils contribute to immunosurveillance, and have a protective role in the development of IBD-associated cancer. For example, Zhou et al. reported the presence of a subpopulation of neutrophils, namely CD177+ neutrophils, that have tumor-suppressor properties. These neutrophils suppressed tumorigenesis and epithelial proliferation demonstrated by increased expression of the proliferation marker Ki67 in CD177−/− mice. In line with this, patients with IBD-associated cancer and CRC patients with high CD177+ neutrophil infiltration had better overall survival compared to the control population [85]. Another study recently showed that neutrophils slow tumor growth by restricting tumor-associated microbiota and IL-17-dependent tumor-associated inflammatory responses[86]. Thus, neutrophils have a dual role in IBD-associated carcinogenesis, being both pro-tumorigenic by generating pro-inflammatory mediators that increase DNA damage and tissue turnover, and anti-tumorigenic by playing an important role in immunosurveillance.
Together with neutrophil infiltration, eosinophils are also commonly present in the inflamed mucosa of IBD patients [87][88]. Activated eosinophils accumulate in the gut of IBD patients and directly contribute to the onset of the inflammatory process in IBD by degranulation[89] . In general, the presence of eosinophils in tumors correlates with a better disease outcome [90][91], and the presence of activated eosinophils has been demonstrated to reduce tumor growth in CRC [92][93]. In IBD-associated cancer, eosinophils seem to play a protective role in tumor development mainly via the effect of the cytokine IL-33. Specifically, IL-33 has been demonstrated to sustain eosinophils by increasing their viability and cytotoxic potentials, making them more effective at fighting malignant cells [94]. However, additional studies are necessary to unravel the function of eosinophils in IBD-associated cancer.

2.2.3 Dendritic Cells

DCs are a heterogeneous group of APCs specialized in the recognition and processing of antigens, and in the activation of naive T lymphocytes. In homeostasis, DCs promote and maintain a tolerogenic immune response. Conversely, in IBD, DCs lose their tolerogenic phenotype and display pro-inflammatory features, causing excessive T-cell responses with the subsequent overload of pro-inflammatory cytokines[95][96][97][98]. This pro-inflammatory milieu may drive cancer formation, yet the subsequent T cell responses also play a key role in cancer immunosurveillance.
Only few studies exist that highlight a specific anti-tumoral function of DCs in IBD-associated cancer. In a mouse model for CAC, IRF8-expressing cDC1s (conventional DCs specialized in activating T CD8+ cells) do not seem to contribute to anti-cancer immune responses [99]. Furthermore, it was shown that alterations in phenotype and function of DCs in IBD could play a role in the onset of IBD-associated cancer. First, it was demonstrated that DCs foster a pro-neoplastic inflammatory environment through expression of the transcription factor T-bet [100]. Additionally, it was demonstrated that DCs may exert anti-inflammatory or immunosuppressive mechanisms in the non-dysplastic mucosa from IBD patients, dampening immunosurveillance and contributing to carcinoma progression. For example, it was recently shown that malignant transformation of dysplastic lesions was accelerated in CAC mice in which the transcription factor Notch 2 was deleted in DCs. The authors further demonstrated that Notch2-deficient DCs displayed differentiation defects and had less CC chemokine receptor (CCR)-7 expression, which impeded the migration to the mesenteric lymph nodes and abolished adequate antigen cross-presentation to CD8+ T cells (Table 1). This may therefore impact immunosurveillance and favor the dysplasia to carcinoma progression in mice [71]. Interestingly, pDCs could also play a role in the development of IBD-associated cancer through the recruitment of MDSCs, as observed in a mouse model for CAC [72]  (Table 1). These MDSCs are known for their suppressor capacity, are increased in several malignancies and have been implicated in tumorigenesis [101][102]. Thus, increased pDCs in IBD are involved in shaping a pro-tumorigenic milieu by recruitment of immunosuppressive cells, including MDSCs. CXCR2-expressing MDSCs are also recruited into the colonic mucosa of AOM/DSS-treated mice, which resulted in inhibition of CD8+ T cell effector functions, thereby accelerating tumor growth [73].
Taken together, DCs in IBD-associated cancer may have an anti-inflammatory role, associated with suppressed immunosurveillance. However, it is noteworthy that most of our knowledge regarding the role of DCs in IBD-associated cancer relies on mouse models. Therefore, more insight into the role of DCs in inflammation-associated colorectal carcinogenesis in humans is necessary.

2.2.4 T cells

The lamina propria intestinal T-cell compartment is mainly composed of effector memory CD4+ resident T cells [103]. They are categorized as CD4+ helper T cells (Th), which are further subdivided into Th1, Th2, Th17 and Treg cells (Figure 3). The first three subtypes are effector T cells that act against intracellular pathogens (Th1), helminth parasites and other extracellular microbes (Th2) and extracellular bacteria and fungi (Th17)[104]. In addition, they actively participate in other non-infectious pathologies, such as allergies, autoimmune diseases or anti-tumor immune responses [104]. Conversely, Tregs are in charge of suppressing and controlling immune responses [105]. Although all these Th subtypes are present in the lamina propria, there is an enrichment of Foxp3+ Tregs and IL-17 producing Th17 cells in the lamina propria under homeostatic conditions [106]. In IBD, however, an imbalance of the homeostatic Th populations has been observed in the gut, with Th1-Th17/Th2 polarization of T CD4+ cell immune responses being involved in IBD pathophysiology [107] .

T cells play a crucial role in immunosurveillance; CD8+ T cells can directly eliminate neoplastic cells, and CD4+ T cells collaborate with macrophages, NK cells and CD8+ T cells to mount anti-tumor immune responses [108][109][110]. In IBD-associated cancer, possible immunosurveillance functions of T cells in dysplastic lesions were postulated, associated with the expression of the co-stimulatory molecule CD80. Specifically, it was demonstrated that inhibition of CD80 signaling in vivo in a CAC mouse model significantly increased the frequency and size of high-grade dysplastic lesions, whereas restoration of CD80 expression decreased colonic dysplasia [111] . Another T-cell related immunological interaction relates to the CD30/CD30L axis. CD30L is expressed on T CD4+-activated cells[112]. Deletion of CD30L in an AOM/DSS-induced CAC mouse model promoted formation of an immunosuppressive tumor microenvironment, characterized by an increased percentage of PD-L1+ MDSCs and tolerogenic macrophages [113].

In addition, an earlier study comparing dysplastic lesions and cancers from patients with and without IBD showed that although IBD-associated dysplasia and cancer was associated with increased CD8+ T cell infiltration, these CD8+ T cells showed less expression of granzyme B and were thus less efficient in killing tumor cells [76] (Table 1). Furthermore, Yu et al. demonstrated that intratumoral CD8+ T cells in CAC mice display increased expression of the inhibitory markers PD-1 and CTLA-4, which may also indicate the presence of exhausted T cells [74]. This suppressive T-cell phenotype may contribute to tumor development, as effector cytokine production (IL-2, IFN-γ) is progressively lost in exhausted T cells [114], dampening effective immune responses against neoplastic cells. Similarly, upregulation of PD-1 expression in T CD8+ intraepithelial lymphocytes in mice subjected to AOM/DSS was identified [75] (Table 1), which was likely induced by repetitive cycles of inflammation. In humans, it was shown that patients with UC-associated dysplasia and cancer had increased expression of the PD-1 ligand PD-L1 on CD8+ T cells, as compared to sporadic CRC. PD-L1 overexpression correlated to chronic inflammation-induced DNA damage, and PD-L1 upregulation was mediated by inflammation-induced upregulation of IRF-1 [115] (Table 1). Whether this exhaustion phenotype on T cells also leads to decreased effector functions of T cells, and thus interferes with their immunosurveillance function, needs further investigation.

Lastly, Tregs have an important immunomodulatory role in limiting excessive inflammatory immune responses. They counteract the inflammatory response, but in the setting of cancer, expansion of the Treg pool may shape an immunosuppressive niche in which tumors can progress (Figure 2). In the context of IBD-associated cancer, studies in the AOM/DSS mouse model have shown that ablation of CD4+Foxp3+ Treg cells suppressed tumor growth, which was associated with increased numbers of CD8+IFN-γ+ Granzyme B-producing effector T cells [77][78] (Table 1). This demonstrates how immunosuppressive Tregs may be involved in the pathophysiology of IBD-associated cancer. Apart from immunosuppressive Tregs, IL17+Foxp3+CD4+ T cells, which can be induced by TGF-β, and IL-2 were identified as a functional proinflammatory Treg subpopulation present in the mucosal tissues of patients with active UC and in patients with UC-associated cancer, but not in non-inflammatory cancers, indicating that this subset of Tregs may also play a role in CAC pathogenesis [116].

Another interesting Treg subset in the setting of intestinal inflammation-induced cancer is the Foxp3+RORγt+ T cell. RORγt is a transcription factor other than Foxp3 which plays a role in Treg and Th17 differentiation. Studies have shown that RORγt+Treg cells promote inflammation and tumorigenesis by production of IL-17n [117] , and they are observed in IBD and IBD-associated dysplastic lesions [118][119] . The tumor-promoting role of these cells has been demonstrated by Treg-specific deletion of RORγt in CAC mice, which resulted in decreased tumor incidence and decreased expression of ki67 and STAT3 in dysplastic lesions [119] ]. These data highlight the potential role for this Treg subset in IBD-associated tumorigenesis.

In summary, T cells exert a crucial function in killing neoplastic cells, but chronic inflammation as observed in IBD may induce an immunosuppressive environment with T-cell exhaustion and excessive Treg cell recruitment, which prevents adequate immunosurveillance and promotes evolution from non-dysplastic mucosa to dysplasia and/or carcinoma. In addition, pro-inflammatory Treg subpopulations such as IL-17-producing Tregs and Foxp3+RORγt+ Tregs may contribute to cancer development in IBD. It will be interesting to unravel the role of these T cell subsets in IBD-associated dysplasia and cancer in humans.

2.2.5  Innate Lymphoid Cells

Innate lymphoid cells (ILCs) are a relatively recently discovered group of innate immune cells with diverse and important functions. They are generally classified in three types, with type 1 ILCs including NK cells. A large body of evidence demonstrates their role in IBD pathophysiology [120] . In line with this, patients with Crohn’s disease have increased numbers of NK cells in the small intestinal epithelial compartment [121] and colonic lamina propria [122].

Apart from their role in inflammation, NK cells have important anti-tumorigenic functions and play a pivotal role in clearing cancer cells [123][124]. In IBD-associated cancer, it has been proposed that NK cells participate in anti-tumor immunity through IL-15 stimulation produced by CD11c+ DCs [125]. Specifically, AOM/DSS-treated mice that deleted IL-15 showed reduced survival and higher tumor incidence. Conversely, reconstitution of IL-15 expression selectively in CD11c+ DCs restored NK cells and CD8+ T-cell compartments, with a subsequent reduction in tumor burden.

In the setting of chronic inflammation, NK cell immunosurveillance capacity may be compromised. In a recent study that addressed metabolic and functional profile of blood circulating NK cells in IBD patients, it was demonstrated that these NK cells produce pro-inflammatory cytokines such as IL-17A and TNF-α ex vivo, but they show limited killing capacity and defective mitochondrial activity [79] (Table 1). It could be hypothesized that such defects in NK cell killing capacity as observed in IBD patients might contribute to decreased immunosurveillance.

Additionally, type 3 ILCs (ILC3s), the innate counterparts of Th17 cells from the adaptive immune system, may be involved in IBD-associated cancer formation. ILC3s secrete cytokines including IL-23, IL-17 and IL-22, all of which have pro-tumorigenic effects [126][127][128] . Accumulation of IL-17+ IL-22+ ILC3s was identified in the colonic mucosa from CAC mice. The authors demonstrated the contribution of these cells to tumorigenesis in the context of UC, since its depletion blocks the development of invasive cancer lesions from dysplastic precursors. Further mechanistic analyses showed that IL-22 produced by colonic ILC3s in CAC mice acts on IECs to induce STAT3 phosphorylation [129]. Given the already known pro-cancer effect of STAT3 immune signaling [130], this study demonstrates an active role of ILCs in dampening anti-tumoral immune responses.

Thus, even though some ILCs, such as NK cells, are vital for mounting adequate anti-tumor immune responses, other ILCs including ILC3s may have a pro-tumorigenic effects via secretion of pro-inflammatory cytokines.

3. Conclusions

Long-standing chronic inflammation as observed in the intestinal mucosa of IBD patients increases the risk of CRC. The genetic and molecular changes in IECs of IBD-associated cancers are well characterized, and the role of immune cell-derived pro-inflammatory mediators has been studied extensively, mostly using mouse models.

Less studied potential mechanisms of CAC are the anti-inflammatory/immunosuppressive pathways that emerge during long lasting inflammation, which may create a niche for tumors to grow. It is already well-known that cancers can promote an immunosuppressive microenvironment favoring its own growth and progression. In recent years, this phenomenon has gained more attention, mainly due to the noticeable anti-tumor effects of immune checkpoint inhibitors, which revert to this immunosuppressive state and activate the immune system. Here, we provide an overview of different immune cells that are recruited into the inflamed mucosa of IBD patients and describe how these immune cells impact cancer development, either by anti- or pro-tumorigenic effects. For example, increased expression of T-cell inhibitory receptors such as PD-1 and CTLA-4 have been observed in intratumoral CD4+ and CD8+ T cells lesions in mouse models for inflammation-driven colorectal cancer, indicating that T-cell suppression may be involved in the etiology of IBD-associated cancer. Although there are only limited data in humans, the chronic inflammation-induced immunosuppressive environment may thus be another mechanism driving colitis-associated cancer, not only by induction of dysfunctional, exhausted T cells, but also by the recruitment of Tregs, MDSCs and other suppressor cells into the inflamed intestinal mucosa.

It is important to understand the immunosuppressive mechanisms that evolve during chronic inflammation and may be involved in cancer development by allowing cancers to evade anti-tumor immune responses. This is especially the case for patients at high risk for developing IBD-associated dysplasia and cancer, such as patients with IBD and PSC. Additionally, better understanding of the mechanisms involved may dictate the choice of immunosuppressive drugs used in these patients.

References

  1. Romano, M.; De Francesco, F.; Zarantonello, L.; Ruffolo, C.; Ferraro, G.A.; Zanus, G.; Giordano, A.; Bassi, N.; Cillo, U.; From Inflammation to Cancer in Inflammatory Bowel Disease: Molecular Perspectives. Anticancer Research 2016, 36, 1447-1460.
  2. Saraggi, D.; Fassan, M.; Mescoli, C.; Scarpa, M.; Valeri, N.; Michielan, A.; D’Incá, R.; Rugge, M.; The molecular landscape of colitis-associated carcinogenesis. Digestive Liver Diseases 2017, 49, 326-330.
  3. Okayasu, I.; Development of ulcerative colitis and its associated colorectal neoplasia as a model of the organ-specific chronic inflammation-carcinoma sequence. Pathol. Int 2012, 62, 368-380.
  4. Lakatos, P.L.; Lakatos, L.; Risk for colorectal cancer in ulcerative colitis: Changes, causes and management strategies.. World J. Gastroenterol 2008, 14, 3937–3947.
  5. Fantini, M.C.; Guadagni, I.; From inflammation to colitis-associated colorectal cancer in inflammatory bowel disease: Pathogenesis and impact of current therapies.. Dig. Liver Dis 2021, 53, 558–565.
  6. Lennerz, J.K.; Van Der Sloot, K.W.J.; Le, L.P.; Batten, J.M.; Han, J.Y.; Fan, K.C.; Siegel, C.A.; Srivastava, A.; Park, Y.; Chen, J.-H.; et al.et al. Lennerz, J.K.Van Der Sloot, K.W.J.Le, L.P.Batten, J.M.Han, J.Y.Fan, K.6. Lennerz, J.K.Van Der Sloot, K.W.J.Le, L.P.Batten, J.M.Han, J.Y.Fan, K.C.Siegel, C.A.Srivastava, A.Park, Y.Chen, J.-H.et al. C.Siegel, C.A.Srivastava, A.Park, Y.Chen, J.-H.et al. Colorectal cancer in Crohn’s colitis is comparable to sporadic colorectal cancer. Int. J. Colorectal. Dis 2016, 31, 973–982.
  7. Olén, O.; Erichsen, R.; Sachs, M.C.; Pedersen, L.; Halfvarson, J.; Askling, J.; Ekbom, A.; Sørensen, H.T.; Ludvigsson, J.F.; Colorectal cancer in ulcerative colitis: A Scandinavian population-based cohort study.. Lancet 2020, 395, 123–131.
  8. de Campos Silva, E.F.; Baima, J.P.; de Barros, J.R.; Tanni, S.E.; Schreck, T.; Saad-Hossne, R.; Sassaki, L.Y.; Risk factors for ulcerative colitis-associated colorectal cancer: A retrospective cohort study. . Medicine 2020, 99, e21686.
  9. Rogler, G.; Chronic ulcerative colitis and colorectal cancer. . Cancer Lett 2014, 345, 235–241.
  10. Yvellez, O.V.; Rai, V.; Sossenheimer, P.H.; Hart, J.; Turner, J.R.; Weber, C.; El Jurdi, K.; Rubin, D.T.; Cumulative Histologic Inflammation Predicts Colorectal Neoplasia in Ulcerative Colitis: A Validation Study. Inflamm. Bowel Dis 2021, 27, 203–206.
  11. Porter, R.J.; Arends, M.J.; Churchhouse, A.M.D.; Din, S; Inflammatory bowel disease-associated colorectal cancer: Translational risks from mechanisms to medicines. J. Crohns Colitis 2021, Online ahead of print, Online ahead of print.
  12. Low, D.; Mino-Kenudson, M.; Mizoguchi, E.; Recent advancement in understanding colitis-associated tumorigenesis. Inflamm. Bowel Dis 2014, 20, 2115–2123.
  13. Beaugerie, L.; Itzkowitz, S.H.; Cancers complicating inflammatory bowel disease. N. Engl. J. Med. 2015, 372, 1441–1452.
  14. Dulai, P.S.; Sandborn, W.J.; Gupta, S.; Colorectal Cancer and Dysplasia in Inflammatory Bowel Disease: A Review of Disease Epidemiology, Pathophysiology, and Management. Cancer Prev. Res 2016, 9, 887–894.
  15. Du, L.; Kim, J.J.; Shen, J.; Chen, B.; Dai, N.; KRAS and TP53 mutations in inflammatory bowel disease-associated colorectal cancer: A meta-analysis. Oncotarget 2017, 8, 22175–22186.
  16. Osawa, E.; Nakajima, A.; Fujisawa, T.; Kawamura, Y.I.; Toyama-Sorimachi, N.; Nakagama, H.; Dohi, T.; Predominant T helper type 2-inflammatory responses promote murine colon cancers. Int. J. Cancer 2006, 118, 2232–2236.
  17. Jauch, D.; Martin, M.; Schiechl, G.; Kesselring, R.; Schlitt, H.J.; Geissler, E.K.; Fichtner-Feigl, S; Interleukin 21 controls tumour growth and tumour immunosurveillance in colitis-associated tumorigenesis in mice. Gut 2011, 60, 1678–1686.
  18. Punkenburg, E.; Vogler, T.; Büttner, M.; Amann, K.; Waldner, M.; Atreya, R.; Abendroth, B.; Mudter, J.; Merkel, S.; Gallmeier, E.; et al.et al. Batf-dependent Th17 cells critically regulate IL-23 driven colitis-associated colon cancer. Gut 2016, 65, 1139–1150.
  19. Matsumoto, S.; Hara, T.; Mitsuyama, K.; Yamamoto, M.; Tsuruta, O.; Sata, M.; Scheller, J.; Rose-John, S.; Kado, S.I.; Takada, T; et al. Essential roles of IL-6 trans-signaling in colonic epithelial cells, induced by the IL-6/soluble-IL-6 receptor derived from lamina propria macrophages, on the development of colitis-associated premalignant cancer in a murine model. J. Immunol 2010, 184, 1543–1551.
  20. Yu, H.; Lin, L.; Zhang, Z.; Zhang, H.; Hu, H.; Targeting NF-κB pathway for the therapy of diseases: Mechanism and clinical study. Signal. Transduct. Target. Ther 2020, 5, 209.
  21. Sun, S.C.; The non-canonical NF-κB pathway in immunity and inflammation. Nat. Rev. Immunol 2017, 17, 545–558.
  22. Atreya, I.; Atreya, R.; Neurath, M.F; NF-kappaB in inflammatory bowel disease. J. Intern. Med 2008, 263, 591–596.
  23. Schottelius, A.J.; Baldwin, A.S.Jr; A role for transcription factor NF-kappa B in intestinal inflammation. Int. J. Colorectal. Dis 1999, 14, 18–28.
  24. Viennois, E.; Chen, F.; Merlin, D; NF-κB pathway in colitis-associated cancers. Transl. Gastrointest. Cancer 2013, 2, 21–29.
  25. Greten, F.R.; Eckmann, L.; Greten, T.F.; Park, J.M.; Li, Z.W.; Egan, L.J.; Kagnoff, M.F.; Karin, M; IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004, 118, 285–296.
  26. Allen, I.C.; Wilson, J.E.; Schneider, M.; Lich, J.D.; Roberts, R.A.; Arthur, J.C.; Woodford, R.M.T.; Davis, B.K.; Uronis, J.M.; Herfarth, H.H.; et al.et al. NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-κB signaling. Immunity 2012, 36, 742–754.
  27. Kumar, A.; Chatterjee, I.; Gujral, T.; Alakkam, A.; Coffing, H.; Anbazhagan, A.N.; Borthakur, A.; Saksena, S.; Gill, R.K.; Alrefai, W.A.; et al.et al. Activation of Nuclear Factor-κB by Tumor Necrosis Factor in Intestinal Epithelial Cells and Mouse Intestinal Epithelia Reduces Expression of the Chloride Transporter SLC26A3. Gastroenterology 2017, 153, 1338–1350.
  28. Wang, Z.; Wu, X.; Wang, C.L.; Wang, L.; Sun, C.; Zhang, D.B.; Liu, J.L.; Liang, Y.N.; Tang, D.X.; Tang, Z.S.; et al. Tryptanthrin Protects Mice against Dextran Sulfate Sodium-Induced Colitis through Inhibition of TNF-α/NF-κB and IL-6/STAT3 Pathways. Molecules 2018, 23, 1062.
  29. Grivennikov, S.I.; Inflammation and colorectal cancer: Colitis-associated neoplasia. Semin. Immunopathol 2013, 35, 229–244.
  30. 115. Ba, H.; Jiang, R.; Zhang, M.; Yin, B.; Wang, J.; Li, Z.; Li, B.; Zhou, X.; Suppression of Transmembrane Tumor Necrosis Factor Alpha Processing by a Specific Antibody Protects Against Colitis-Associated Cancer. Front. Immunol 2021, 12, 687874.
  31. Zidi, I.; Mestiri, S.; Bartegi, A.; Amor, N.B.; TNF-alpha and its inhibitors in cancer. Med. Oncol 2010, 27, 185–198.
  32. Caspersen, S.; Elkjaer, M.; Riis, L.; Pedersen, N.; Mortensen, C.; Jess, T.; Sarto, P.; Hansen, T.S.; Wewer, V.; Bendtsen, F.; et al.et al. Infliximab for inflammatory bowel disease in Denmark 1999-2005: Clinical outcome and follow-up evaluation of malignancy and mortality. Clin. Gastroenterol. Hepatol 2008, 6, 1212–1217.
  33. Schnitzler, F.; Fidder, H.; Ferrante, M.; Noman, M.; Arijs, I.; Van Assche, G.; Hoffman, I.; Van Steen, K.; Vermeire, S.; Rutgeerts, P.; et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn’s disease: Results from a single-centre cohort. . Gut 2009, 58, 492–500.
  34. Neurath, M.F.; New targets for mucosal healing and therapy in inflammatory bowel diseases.. Mucosal Immunol 2014, 7, 6–19.
  35. Li, Y.; de Haar, C.; Chen, M.; Deuring, J.; Gerrits, M.M.; Smits, R.; Xia, B.; Kuipers, E.J.; van der Woude, C.J.; Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis. Gut 2010, 59, 227–235.
  36. Grivennikov, S.; Karin, E.; Terzic, J.; Mucida, D.; Yu, G.-Y.; Vallabhapurapu, S.; Scheller, J.; Rose-John, S.; Cheroutre, H.; Eckmann, L.; et al.et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 2009, 15, 103–113.
  37. Backert, I.; Koralov, S.; Wirtz, S.; Kitowski, V.; Billmeier, U.; Martini, E.; Hofmann, K.; Hildner, K.; Wittkopf, N.; Brecht, K.; et al.et al. STAT3 activation in Th17 and Th22 cells controls IL-22-mediated epithelial host defense during infectious colitis. J. Immunol 2014, 193, 3779–3791.
  38. Nguyen, P.M.; Putoczki, T.L.; Ernst, M.; STAT3-Activating Cytokines: A Therapeutic Opportunity for Inflammatory Bowel Disease? . J. Interferon Cytokine Res 2015, 35, 340–350.
  39. Pickert, G.; Neufert, C.; Leppkes, M.; Zheng, Y.; Wittkopf, N.; Warntjen, M.; Lehr, H.-A.; Hirth, S.; Weigmann, B.; Wirtz, S.; et al.et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med 2009, 206, 1465–1472.
  40. Yu, L.Z.; Wang, H.Y.; Yang, S.P.; Yuan, Z.P.; Xu, F.Y.; Sun, C.; Shi, R.H; Expression of interleukin-22/STAT3 signaling pathway in ulcerative colitis and related carcinogenesis.. World J. Gastroenterol 2013, 19, 2638–2649.
  41. Jiang, R.; Wang, H.; Deng, L.; Hou, J.; Shi, R.; Yao, M.; Gao, Y.; Yao, A.; Wang, X.; Yu, L.; et al.et al. IL-22 is related to development of human colon cancer by activation of STAT3. BMC Cancer 2013, 13, 59.
  42. Pan, M.G.; Xiong, Y.; Chen, F; NFAT gene family in inflammation and cancer. . Curr. Mol. Med 2013, 13, 543–554.
  43. Liu, Z.; Lee, J.; Krummey, S.; Lu, W.; Cai, H.; Lenardo, M.J.; The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat. Immunol 2011, 12, 1063–1070.
  44. 129. Weigmann, B.; Lehr, H.A.; Yancopoulos, G.; Valenzuela, D.; Murphy, A.; Stevens, S.; Schmidt, J.; Galle, P.R.; Rose-John, S.; Neurath, M.F.; et al. The transcription factor NFATc2 controls IL-6-dependent T cell activation in experimental colitis. J. Exp. Med 2008, 205, 2099–2110.
  45. Gerlach, K.; Daniel, C.; Lehr, H.A.; Nikolaev, A.; Gerlach, T.; Atreya, R.; Rose-John, S.; Neurath, M.F.; Weigmann, B.; Transcription factor NFATc2 controls the emergence of colon cancer associated with IL-6-dependent colitis.. Cancer Res 2012, 72, 4340–4350.
  46. Lin, Y.; Koumba, M.H.; Qu, S.; Wang, D.; Lin, L.; Blocking NFATc3 ameliorates azoxymethane/dextran sulfate sodium induced colitis-associated colorectal cancer in mice via the inhibition of inflammatory responses and epithelial-mesenchymal transition. Cell. Signal 2020, 74, 109707.
  47. Schmitt, H.; Neurath, M.F.; Atreya, R.; Role of the IL23/IL17 Pathway in Crohn’s Disease. Front. Immunol 2021, 12, 622934.
  48. Bunte, K.; Beikler, T; Th17 Cells and the IL-23/IL-17 Axis in the Pathogenesis of Periodontitis and Immune-Mediated Inflammatory Diseases. Int. J. Mol. Sci 2019, 20, 3394.
  49. Qi, H.; Yang, H.; Xu, G.; Ren, J.; Hua, W.; Shi, Y.; Torsvik, M.; Florholmen, J.; Cui, G.; Therapeutic efficacy of IL-17A antibody injection in preventing the development of colitis associated carcinogenesis in mice. Immunobiology 2015, 220, 54–59.
  50. Eken, A.; Oukka, M.. Interleukin 23 in IBD Pathogenesis; Samuel Huber, IntechOpen: London, United Kingdom, 2016; pp. pp. 93–123.
  51. Hyun, Y.S.; Han, D.S.; Lee, A.R.; Eun, C.S.; Youn, J.; Kim, H.Y; Role of IL-17A in the development of colitis-associated cancer. Carcinogenesis 2012, 33, 931–936.
  52. Fiorino, G.; Allocca, M.; Correale, C.; Roda, G.; Furfaro, F.; Loy, L.; Zilli, A.; Peyrin-Biroulet, L.; Danese, S.; Positioning ustekinumab in moderate-to-severe ulcerative colitis: New kid on the block. . Expert Opin. Biol. Ther 2020, 20, 421–427.
  53. Argollo, M.C.; Allocca, M.; Furfaro, F.; Peyrin-Biroulet, L.; Danese, S; . Interleukin-23 Blockers: Born to be First-line Biologic Agents in Inflammatory Bowel Disease?. Curr. Pharm. Des 2019, 25, 25–31.
  54. Smyth, M.J.; Taniguchi, M.; Street, S.E; The anti-tumor activity of IL-12: Mechanisms of innate immunity that are model and dose dependent.. J. Immunol 2000, 165, 2665–2670.
  55. Teng, M.W.; Vesely, M.D.; Duret, H.; McLaughlin, N.; Towne, J.E.; Schreiber, R.D.; Smyth, M.J.; Opposing roles for IL-23 and IL-12 in maintaining occult cancer in an equilibrium state. Cancer Res 2012, 72, 3987–3996.
  56. Bain, C.C.; Mowat, A.M.; Macrophages in intestinal homeostasis and inflammation. Immunol. Rev 2014, 260, 102–117.
  57. Mowat, A.M; To respond or not to respond—A personal perspective of intestinal tolerance. Nat. Rev. Immunol 2018, 18, 405–415.
  58. Bain, C.C.; Scott, C.L.; Uronen-Hansson, H.; Gudjonsson, S.; Jansson, O.; Grip, O.; Guilliams, M.; Malissen, B.; Agace, W.W.; Mowat, A.M; et al. Resident and pro-inflammatory macrophages in the colon represent alternative contex.xt-dependent fates of the same Ly6Chi monocyte precursors. Mucosal Immunol 2013, 6, 498–510.
  59. Thiesen, S.; Janciauskiene, S.; Uronen-Hansson, H.; Agace, W.; Högerkorp, C.-M.; Spee, P.; Håkansson, K.; Grip, O.; CD14(hi)HLA-DR(dim) macrophages, with a resemblance to classical blood monocytes, dominate inflamed mucosa in Crohn’s disease. J. Leukoc. Biol 2014, 95, 531–541.
  60. Bernardo, D.; Marin, A.C.; Fernández-Tomé, S.; Montalban-Arques, A.; Carrasco, A.; Tristán, E.; Ortega-Moreno, L.; Mora-Gutiérrez, I.; Díaz-Guerra, A.; Caminero-Fernández, R.; et al.et al. Human intestinal pro-inflammatory CD11c(high)CCR2(+)CX3CR1(+) macrophages, but not their tolerogenic CD11c(-)CCR2(-)CX3CR1(-) counterparts, are expanded in inflammatory bowel disease. Mucosal Immunol 2018, 11, 1114–1126.
  61. Dharmasiri, S.; Garrido-Martin, E.M.; Harris, R.J.; Bateman, A.C.; Collins, J.E.; Cummings, J.R.; Sanchez-Elsner, T.; . Intestinal Macrophages Are Involved in the Pathology of Both Ulcerative Colitis and Crohn Disease. Inflamm. Bowel Dis 2021, Online ahead of print., Online ahead of print..
  62. Liu, J.; Geng, X.; Hou, J.; Wu, G; New insights into M1/M2 macrophages: Key modulators in cancer progression. Cancer Cell Int 2021, 21, 389.
  63. Fan, Y.; Mao, R.; Yang, J; NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell 2013, 4, 176–185.
  64. Seyedizade, S.S.; Afshari, K.; Bayat, S.; Rahmani, F.; Momtaz, S.; Rezaei, N.; Abdolghaffari, A.H; Current Status of M1 and M2 Macrophages Pathway as Drug Targets for Inflammatory Bowel Disease. Arch. Immunol. Ther. Exp 2020, 68, 10.
  65. Shin, S.H.; Kadayakkara, D.K.; Bulte, J.W; In Vivo (19)F MR Imaging Cell Tracking of Inflammatory Macrophages and Site-specific Development of Colitis-associated Dysplasia. Radiology 2017, 282, 194–201.
  66. Khan, M.W.; Keshavarzian, A.; Gounaris, E.; Melson, J.E.; Cheon, E.C.; Blatner, N.R.; Chen, Z.E.; Tsai, F.-N.; Lee, G.; Ryu, S.H.; et al.et al. . PI3K/AKT signaling is essential for communication between tissue-infiltrating mast cells, macrophages, and epithelial cells in colitis-induced cancer. Clin. Cancer Res 2013, 19, 2342–2354.
  67. Wang, W.E.I.; Li, X.; Zheng, D.; Zhang, D.; Peng, X.; Zhang, X.; Ai, F.; Wang, X.; Ma, J.; Xiong, W.; et al.et al. Dynamic changes and functions of macrophages and M1/M2 subpopulations during ulcerative colitis-associated carcinogenesis in an AOM/DSS mouse model. Mol. Med. Rep 2015, 11, 2397–2406.
  68. Kvorjak, M.; Ahmed, Y.; Miller, M.L.; Sriram, R.; Coronnello, C.; Hashash, J.G.; Hartman, D.J.; Telmer, C.A.; Miskov-Zivanov, N.; Finn, O.J.; et al.et al. Cross-talk between Colon Cells and Macrophages Increases ST6GALNAC1 and MUC1-sTn Expression in Ulcerative Colitis and Colitis-Associated Colon Cancer. Cancer Immunol. Res 2020, 8, 167–178.
  69. Serbina, N.V.; Salazar-Mather, T.P.; Biron, C.A.; Kuziel, W.A.; Pamer, E.G.; TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 2003, 19, 59–70.
  70. Moreira, T.G.; Horta, L.S.; Gomes-Santos, A.C.; Oliveira, R.P.; Queiroz, N.M.G.P.; Mangani, D.; Daniel, B.; Vieira, A.T.; Liu, S.; Rodrigues, A.M.; et al.et al. CLA-supplemented diet accelerates experimental colorectal cancer by inducing TGF-β-producing macrophages and T cells.. Mucosal Immunol 2019, 12, 188–199.
  71. Wang, L.; Yu, S.; Chan, E.R.; Chen, K.-Y.; Liu, C.; Che, D.; Awadallah, A.; Myers, J.; Askew, D.; Huang, A.Y.; et al.et al. Notch-Regulated Dendritic Cells Restrain Inflammation-Associated Colorectal Carcinogenesis.. Cancer Immunol. Res 2021, 9, 348–361.
  72. Hong, E.-H.; Cho, J.; Ahn, J.-H.; Kwon, B.-E.; Kweon, M.-N.; Seo, S.-U.; Yoon, B.-I.; Chang, S.-Y.; Ko, H.-J.; Plasmacytoid dendritic cells regulate colitis-associated tumorigenesis by controlling myeloid-derived suppressor cell infiltration. Cancer Lett 2020, 493, 102–112.
  73. Katoh, H.; Wang, D.; Daikoku, T.; Sun, H.; Dey, S.K.; Dubois, R.N.; CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis. Cancer Cell 013, 24, 631–644.
  74. Amy, I.Y.; Zhao, L.; Eaton, K.A.; Ho, S.; Chen, J.; Poe, S.; Becker, J.; Gonzalez, A.; McKinstry, D.; Hasso, M.; et al.Mendoza-Castrejon, J. Gut Microbiota Modulate CD8 T Cell Responses to Influence Colitis-Associated Tumorigenesis. Cell Rep 2020, 31, 107471.
  75. Yassin, M.; Sadowska, Z.; Djurhuus, D.; Nielsen, B.; Tougaard, P.; Olsen, J.; Pedersen, A.E; Upregulation of PD-1 follows tumour development in the AOM/DSS model of inflammation-induced colorectal cancer in mice. Immunology 2019, 158, 35–46.
  76. Michael-Robinson, J.; Pandeya, N.; Walsh, M.D.; Biemer-Huttmann, A.-E.; Eri, R.; Buttenshaw, R.; Lincoln, D.; Clouston, A.; Jass, J.; Radford-Smith, G.; et al. Characterization of tumour-infiltrating lymphocytes and apoptosis in colitis-associated neoplasia: Comparison with sporadic colorectal cancer. J. Pathol 2006, 208, 381–387.
  77. Pastille, E.; Bardini, K.; Fleissner, D.; Adamczyk, A.; Frede, A.; Wadwa, M.; Von Smolinski, D.; Kasper, S.; Sparwasser, T.; Gruber, A.D.; et al.et al Transient ablation of regulatory T cells improves antitumor immunity in colitis-associated colon cancer. Cancer Res 2014, 74, 4258–4269.
  78. Olguín, J.E.; Medina-Andrade, I.; Molina, E.; Vázquez, A.; Pacheco-Fernández, T.; Saavedra, R.; Perez-Plasencia, C.; Chirino, Y.I.; Vaca-Paniagua, F.; Arias-Romero, L.E.; et al.et al. Early and Partial Reduction in CD4(+)Foxp3(+) Regulatory T Cells during Colitis-Associated Colon Cancer Induces CD4(+) and CD8(+) T Cell Activation Inhibiting Tumorigenesis. J. Cancer 2018, 9, 239–249..
  79. Zaiatz Bittencourt, V.; Jones, F.; Tosetto, M.; Doherty, G.A.; Ryan, E.J.; Dysregulation of Metabolic Pathways in Circulating Natural Killer Cells Isolated from Inflammatory Bowel Disease Patients. J. Crohns Colitis 2021, 15, 1316–1325.
  80. Therrien, A.; Chapuy, L.; Bsat, M.; Rubio, M.; Bernard, G.; Arslanian, E.; Orlicka, K.; Weber, A.; Panzini, B.; Dorais, J.; et al.et al Recruitment of activated neutrophils correlates with disease severity in adult Crohn’s disease. Clin. Exp. Immunol 2019, 195, 251–264.
  81. Alhmoud, T.; Gremida, A.; Steele, D.C.; Fallahi, I.; Tuqan, W.; Nandy, N.; Ismail, M.; Altamimi, B.A.; Xiong, M.-J.; Kerwin, A.; et al.et al. Outcomes of inflammatory bowel disease in patients with eosinophil-predominant colonic inflammation. BMJ Open Gastroenterol 2020, 7, e000373.
  82. Lin, Y.; Cheng, L.; Liu, Y.; Wang, Y.; Wang, Q.N.; Wang, H.L.; Shi, G.; Li, J.S.; Yang, Q.M.; Chen, S.; et al.et al. Intestinal epithelium-derived BATF3 promotes colitis-associated colon cancer through facilitating CXCL5-mediated neutrophils recruitment. Mucosal Immunol 2021, 14, 187–198.
  83. Wéra, O.; Lancellotti, P.; Oury, C.; The Dual Role of Neutrophils in Inflammatory Bowel Diseases. J. Clin. Med 2016, 5, 118.
  84. Knaapen, A.M.; Schins, R.P.; Polat, D.; Becker, A.; Borm, P.J.; Mechanisms of neutrophil-induced DNA damage in respiratory tract epithelial cells. Mol. Cell Biochem 2002, 234-235, 143–151.
  85. Zhou, G.; Peng, K.; Song, Y.; Yang, W.; Shu, W.; Yu, T.; Yu, L.; Lin, M.; Weigang, S.; Chen, C.; et al.et al. CD177+ neutrophils suppress epithelial cell tumourigenesis in colitis-associated cancer and predict good prognosis in colorectal cancer. Carcinogenesis 2018, 39, 272–282.
  86. Triner, D.; Devenport, S.N.; Ramakrishnan, S.K.; Ma, X.; Frieler, R.A.; Greenson, J.K.; Neutrophils Restrict Tumor-Associated Microbiota to Reduce Growth and Invasion of Colon Tumors in Mice. Gastroenterology 2019, 156, 1467–1482.
  87. Lampinen, M.; Backman, M.; Winqvist, O.; Rorsman, F.; Rönnblom, A.; Sangfelt, P.; Carlson, M.; Different regulation of eosinophil activity in Crohn’s disease compared with ulcerative colitis. J. Leukoc. Biol 2008, 84, 1392–1399.
  88. Leoncini, G.; Villanacci, V.; Marin, M.G.; Crisafulli, V.; Cadei, M.; Antonelli, E.; Leoci, C.; Bassotti, G.; Colonic hypereosinophilia in ulcerative colitis may help to predict the failure of steroid therapy. Tech. Coloproctol 2018, 22, 941–946.
  89. Sastre, B.; Rodrigo-Muñoz, J.M.; Garcia-Sanchez, D.A.; Cañas, J.A.; Del Pozo, V.; Eosinophils: Old Players in a New Game. Clin. Immunol 2018, 28, 289–304.
  90. Hu, G.; Wang, S.; Zhong, K.; Xu, F.; Huang, L.; Chen, W.; Cheng, P.; Tumor-associated tissue eosinophilia predicts favorable clinical outcome in solid tumors: A meta-analysis. BMC Cancer 2020, 20, 454.
  91. Moreira, A.; Leisgang, W.; Schuler, G.; Heinzerling, L.; Eosinophilic count as a biomarker for prognosis of melanoma patients and its importance in the response to immunotherapy. Immunotherapy 2017, 9, 115–121.
  92. Harbaum, L.; Pollheimer, M.J.; Kornprat, P.; Lindtner, R.A.; Bokemeyer, C.; Langner, C; Peritumoral eosinophils predict recurrence in colorectal cancer. Mod. Pathol 2015, 28, 403–413.
  93. Prizment, A.E.; Vierkant, R.; Smyrk, T.C.; Tillmans, L.S.; Lee, J.J.; Sriramarao, P.; Nelson, H.; Lynch, C.F.; Thibodeau, S.N.; Church, T.R.; et al.et al. Tumor eosinophil infiltration and improved survival of colorectal cancer patients: Iowa Women’s Health Study. Mod. Pathol 2016, 29, 516–527.
  94. Kienzl, M.; Hasenoehrl, C.; Valadez-Cosmes, P.; Maitz, K.; Sarsembayeva, A.; Sturm, E.; Heinemann, A.; Kargl, J.; Schicho, R; IL-33 reduces tumor growth in models of colorectal cancer with the help of eosinophils. . Oncoimmunology 2020, 9, 1776059.
  95. Jaensson, E.; Uronen-Hansson, H.; Pabst, O.; Eksteen, B.; Tian, J.; Coombes, J.L.; Berg, P.L.; Davidsson, T.; Powrie, F.; Johansson-Lindbom, B.; et al.et al Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans. J. Exp. Med 2008, 205, 2139–2149.
  96. Baumgart, D.C.; Thomas, S.; Przesdzing, I.; Metzke, D.; Bielecki, C.; Lehmann, S.M.; Lehnardt, S.; Dörffel, Y.; Sturm, A.; Scheffold, A.; et al.et al. Exaggerated inflammatory response of primary human myeloid dendritic cells to lipopolysaccharide in patients with inflammatory bowel disease. Clin. Exp. Immunol 2009, 157, 423–436.
  97. Bakdash, G.; Vogelpoel, L.T.; van Capel, T.M.; Kapsenberg, M.L.; de Jong, E.C.; Retinoic acid primes human dendritic cells to induce gut-homing, IL-10-producing regulatory T cells. Mucosal Immunol 2015, 8, 265–278.
  98. Matsuno, H.; Kayama, H.; Nishimura, J.; Sekido, Y.; Osawa, H.; Barman, S.; Ogino, T.; Takahashi, H.; Haraguchi, N.; Hata, T.; et al.et al. CD103+ Dendritic Cell Function Is Altered in the Colons of Patients with Ulcerative Colitis. Inflamm. Bowel Dis 2017, 23, 1524–1534.
  99. Pool, L. Intestinal Classical Dendritic in T Cell Induced Colitis and Colitis Associated Colorectal Cancer; DTU Nanotech, Technical University of Denmark: Lyngby, Denmark, 2018.
  100. Garrett, W.S.; Punit, S.; Gallini, C.A.; Michaud, M.; Zhang, D.; Sigrist, K.S.; Lord, G.M.; Glickman, J.N.; Glimcher, L.H; Colitis-associated colorectal cancer driven by T-bet deficiency in dendritic cells. Cancer Cell 2009, 16, 208–219.
  101. Yang, Y.; Li, C.; Liu, T.; Dai, X.; Bazhin, A.V.; Myeloid-Derived Suppressor Cells in Tumors: From Mechanisms to Antigen Specificity and Microenvironmental Regulation. Front. Immunol 2020, 11, 1371.
  102. Groth, C.; Arpinati, L.; Shaul, M.; Winkler, N.; Diester, K.; Gengenbacher, N.; Weber, R.; Arkhypov, I.; Lasser, S.; Petrova, V.; et al.et al. Blocking Migration of Polymorphonuclear Myeloid-Derived Suppressor Cells Inhibits Mouse Melanoma Progression. Cancers 2021, 13, 726.
  103. James, S.P.; Kwan, W.C.; Sneller, M.C; T cells in inductive and effector compartments of the intestinal mucosal immune system of nonhuman primates differ in lymphokine mRNA expression, lymphokine utilization, and regulatory function. J. Immunol 1990, 144, 1251–1256.
  104. Tindemans, I.; Joosse, M.E.; Samsom, J.N; Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD. Cells 2020, 9, 110.
  105. Okeke, E.B.; Uzonna, J.E; The Pivotal Role of Regulatory T Cells in the Regulation of Innate Immune Cells. Front. Immunol 2019, 10, 680.
  106. van Wijk, F.; Cheroutre, H; Mucosal T cells in gut homeostasis and inflammation. Expert Rev. Clin. Immunol 2010, 6, 559–566.
  107. Geremia, A.; Biancheri, P.; Allan, P.; Corazza, G.R.; Di Sabatino, A; Innate and adaptive immunity in inflammatory bowel disease. Autoimmun. Rev 2014, 13, 3–10.
  108. Gonzalez, H.; Hagerling, C.; Werb, Z; Roles of the immune system in cancer: From tumor initiation to metastatic progression. Genes Dev 2018, 32, 1267–1284.
  109. Rao, S.; Gharib, K.; Han, A.. Chapter Five—Cancer Immunosurveillance by T Cells. In International Review of Cell and Molecular Biology; Galluzzi, L., Rudqvist, N.-P., Eds, Eds.; Academic Press: San Diego, CA, USA, 2019; pp. pp. 149–73.
  110. Ostroumov, D.; Fekete-Drimusz, N.; Saborowski, M.; Kühnel, F.; Woller, N; CD4 and CD8 T lymphocyte interplay in controlling tumor growth. Cell Mol. Life Sci 2018, 75, 689–713.
  111. Scarpa, M.; Brun, P.; Scarpa, M.; Morgan, S.; Porzionato, A.; Kotsafti, A.; Bortolami, M.; Buda, A.; D’Incà, R.; Macchi, V.; et al.et al. CD80-CD28 signaling controls the progression of inflammatory colorectal carcinogenesis. Oncotarget 2015, 6, 20058–20069.
  112. Tang, C.; Yamada, H.; Shibata, K.; Muta, H.; Wajjwalku, W.; Podack, E.R.; Yoshikai, Y; A novel role of CD30L/CD30 signaling by T-T cell interaction in Th1 response against mycobacterial infection. J. Immunol 2008, 181, 6316–6327.
  113. Wang, X.; Gao, Y.; Zhang, X.; Wang, X.; Wang, B.; Meng, X.; Yoshikai, Y.; Wang, Y.; Sun, X.; CD30L/CD30 signaling regulates the formation of the tumor immune microenvironment and inhibits intestinal tumor development of colitis-associated colon cancer in mice. Immunopharmacol. 2020, 84, 106531.
  114. Catakovic, K.; Klieser, E.; Neureiter, D.; Geisberger, R.; T cell exhaustion: From pathophysiological basics to tumor immunotherapy. Cell Commun. Signal 2017, 15, 1.
  115. Ozawa, N.; Yokobori, T.; Osone, K.; Katayama, C.; Suga, K.; Komine, C.; Shibasaki, Y.; Shiraishi, T.; Okada, T.; Kato, R.; et al.et al. PD-L1 upregulation is associated with activation of the DNA double-strand break repair pathway in patients with colitic cancer. Sci. Rep 2021, 11, 13077.
  116. Kryczek, I.; Wu, K.; Zhao, E.; Wei, S.; Vatan, L.; Szeliga, W.; Huang, E.; Greenson, J.; Chang, A.; Rolinski, J.M.; et al.et al .; Vatan, L.; Szeliga, W.; Huang, E.; Greenson, J.; Chang, A.; Rolinski, J.M.; et al.. J. Immunol 2011, 186, 4388–4395.
  117. Li, L.; Boussiotis, V.A; The role of IL-17-producing Foxp3+ CD4+ T cells in inflammatory bowel disease and colon cancer. Clin. Immunol 2013, 148, 246–253.
  118. Ueno, A.; Jijon, H.; Chan, R.; Ford, K.; Hirota, C.; Kaplan, G.G.; Beck, P.L.; Iacucci, M.; Gasia, M.F.; Barkema, H.W.; et al.et al Increased prevalence of circulating novel IL-17 secreting Foxp3 expressing CD4+ T cells and defective suppressive function of circulating Foxp3+ regulatory cells support plasticity between Th17 and regulatory T cells in inflammatory bowel disease patients. Inflamm. Bowel Dis 2013, 19, 2522–2534.
  119. Rizzo, A.; Di Giovangiulio, M.; Stolfi, C.; Franzè, E.; Fehling, H.-J.; Carsetti, R.; Giorda, E.; Colantoni, A.; Ortenzi, A.; Rugge, M.; et al.et al. RORγt-Expressing Tregs Drive the Growth of Colitis-Associated Colorectal Cancer by Controlling IL6 in Dendritic Cells. Cancer Immunol Res 2018, 6, 1082–1092.
  120. Saez, A.; Gomez-Bris, R.; Herrero-Fernandez, B.; Mingorance, C.; Rius, C.; Gonzalez-Granado, J.M; Innate Lymphoid Cells in Intestinal Homeostasis and Inflammatory Bowel Disease. Int. J. Mol. Sci 2021, 22, 7618.
  121. Hosomi, S.; Grootjans, J.; Tschurtschenthaler, M.; Krupka, N.; Matute, J.D.; Flak, M.B.; Martinez-Naves, E.; Del Moral, M.G.; Glickman, J.N.; Ohira, M.; et al.et al. Intestinal epithelial cell endoplasmic reticulum stress promotes MULT1 up-regulation and NKG2D-mediated inflammation. J. Exp. Med 2017, 214, 2985–2997.
  122. Liu, Z.; Yang, L.; Cui, Y.; Wang, X.; Guo, C.; Huang, Z.; Kan, Q.; Liu, Z.; Liu, Y; Il-21 enhances NK cell activation and cytolytic activity and induces Th17 cell differentiation in inflammatory bowel disease. Inflamm Bowel Dis 2009, 15, 1133–1144.
  123. Waldhauer, I.; Steinle, A; NK cells and cancer immunosurveillance. Oncogene 2008, 27, 5932–5943.
  124. Wu, S.Y.; Fu, T.; Jiang, Y.Z.; Shao, Z.M; Natural killer cells in cancer biology and therapy. Mol. Cancer 2020, 19, 120.
  125. Bahri, R.; Pateras, I.S.; D’Orlando, O.; Goyeneche-Patino, D.A.; Campbell, M.; Polansky, J.K.; Sandig, H.; Papaioannou, M.; Evangelou, K.; Foukas, P.G.; et al.et al. IL-15 suppresses colitis-associated colon carcinogenesis by inducing antitumor immunity. Oncoimmunology 2015, 4, e1002721.
  126. Kuen, D.S.; Kim, B.S.; Chung, Y; IL-17-Producing Cells in Tumor Immunity: Friends or Foes? . Immune Netw 2020, 20, e6.
  127. Yan, J.; Smyth, M.J.; Teng, M.W.L; Interleukin (IL)-12 and IL-23 and Their Conflicting Roles in Cancer. Cold Spring Harb Perspect Biol 2018, 10, a028530.
  128. Eyerich, K.; Dimartino, V.; Cavani, A; IL-17 and IL-22 in immunity: Driving protection and pathology. Eur. J. Immunol 2017, 47, 607–614.
  129. Kirchberger, S.; Royston, D.J.; Boulard, O.; Thornton, E.; Franchini, F.; Szabady, R.L.; Harrison, O.; Powrie, F; Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J. Exp. Med 2013, 210, 917–931.
  130. Tolomeo, M.; Cascio, A; The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy. Int. J. Mol. Sci 2021, 22, 603.
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Subjects: Gastroenterology & Hepatology; Oncology; Immunology
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Sofía Frigerio
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