Species of Gut Bacteria Associated with Antitumor Immunity: History
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Both preclinical and clinical studies have demonstrated that the modulation of gut microbiota could be a promising strategy for enhancing antitumor immune responses and reducing resistance to immunotherapy in cancer. Various mechanisms, including activation of pattern recognition receptors, gut commensals-produced metabolites and antigen mimicry, have been revealed. Different gut microbiota modulation strategies have been raised, such as fecal microbiota transplantation, probiotics, and dietary selection.

  • gut microbiota
  • antitumor
  • immunotherapy
  • probiotics

1. Bacteria Species Associated with Favorable Modulation in Antitumor Immunity

1.1. Bifidobacterium spp.

Bifidobacterium is a genus of Gram-positive anaerobic bacteria; it may be the most well-known probiotic because of its friendly inhabitation of the human gut. The growth of Bifidobacterium strains in the gut can expel other non-helpful microorganisms so as to keep people healthy. Early in 2015, Sivan et al. reported that Bifidobacterium has favorable properties for the antitumor immune response. In a preclinical study, they found that using mice purchased from different facilities to establish tumor models resulted in different tumor growth rates with distinct tumor-infiltrating lymphocyte profiles. The mice from Jackson Laboratory had a slower tumor growth rate than the mice from Taconic Farm using the same procedures. This difference can be abolished by cohousing the mice. More interestingly, a FMT from Jackson donor mice to Taconic recipient mice before tumor inoculation could improve effector CD8+ T cell infiltration into the tumor and retard tumor progression in the recipient mice. A gut microbiota analysis via 16s ribosomal RNA gene sequencing showed that the Bifidobacterium operational taxonomic unit (OTU) is 400 times more abundant in Jackson mice than Taconic mice [1].
A recent study reported that Bifidobacterium facilitates CD47-based immunotherapy through accumulation in the tumor microenvironment (TME). The systemic administration of mixed species of Bifidobacterium led to the accumulation of Bifidobacterium spp. in the tumor, which reversed the resistance of anti-CD47 immunotherapy in a colon cancer mouse model. The mechanistic study showed that in the mice deprived of the stimulator of interferon genes (STING), which regulates the expression of type I interferon (IFN), the administration of Bifidobacterium could not sufficiently enhance the antitumor activity produced by anti-CD47. This proved that Bifidobacterium worked together with STING in the dendritic cells (DCs) to enhance the antigen presentation on DCs, overcoming the CD47 signal and accumulating more T cells [2].
In the consideration of gut microbiota as a large microbial ecosystem, some researchers proposed that the modulation of an individual gut microbiota species is not enough to improve the efficacy of immunotherapy for cancer or reverse the resistance towards immune response; perhaps a modulation targeting a group of gut microbiota species will be more feasible for altering the response to the treatments. However, researchers have found an increase in Bifidobacterium could mediate the entire commensal community. One investigation associated Bifidobacterium with a change in the other microbial species in the gut, such as an increased level of Lactobacillus. It helps ameliorate adverse effects induced by cytotoxic T-lymphocyte-associated protein 4 (CTLA4) blockade. Mechanistically, unlike cells containing Treg, Treg-depleted cells have shown that there was no increase in the gut microbiota species number in the presence of Bifidobacterium. This led to the understanding that Bifidobacterium alter the microbiota composition in conjunction with Treg cells [3].
In a clinical study, researchers found more abundant Bifidobacterium in patients with melanoma who responded to a treatment of programmed cell death protein 1 (PD1) blockade compared to patients who failed to respond to PD1 blockade [4]. The Bifidobacterium species B. longum was reported to be enriched in patients with non-small cell lung carcinoma (NSCLC) who responded to anti-PD1 treatment accompanied by higher levels of memory CD8+ T cells and natural killer (NK) T cells in their blood [5]. Even given the lack of direct evidence and mechanistic studies, these findings suggest Bifidobacterium are beneficial for the antitumor immune response. On the other hand, it has been indicated that Bifidobacterium spp. help ameliorate anti-CTLA4 immunotherapy-induced colitis. Administration of Bifidobacterium reduced the weight loss caused by CTLA4 blockade accompanied with decreased inflammatory cytokine levels without compromising anti-CTLA4’s therapeutic effect in a mouse model [6].
Despite all the data above, the challenge remains to be the further identification of different Bifidobacterium strains, since most studies were performed at the level of the gut microbiota genus, as well as the illustration of the underlying molecular mechanisms. In a study using two strains of Bifidobacterium breve (JCM92 and Bb03) collected from two different sources, the significant genetical differences between these two B. breve strains resulted in differences in the outcome of an antitumor treatment. Similar to the scenario above, although both strains enhanced the antitumor immune response, e.g., increased T cell activation, only the JCM92 strain boosted the activity of the chemotherapy drug oxaliplatin, CTLA4 blockade, and programmed death-ligand 1 (PD-L1) blockade. However, further analysis is needed to determine the mechanisms behind this observation. Studying the genes of B. breve, it was seen that the JCM92 strain but not Bb03 had genes that stimulated RNA, amino acid, and amino-sugar metabolic processes, which are known to contribute to antitumor activities through acid-degrading enzymes [7]. In another study, investigators observed that Bifidobacterium strains produce inosine. Inosine, a metabolite of the human body with multiple functions, has a critical role in immune activation. Inosine greatly improves the expression of tumor antigens, allowing cytotoxic immune cells to quickly identify and eradicate tumor cells. The study demonstrated that the presence of inosine increased the level of IFN-γ and TNF-α, which further increased tumor antigen presentation and aided T cell activity. Additionally, studies in a mouse model showed that inosine acted on adenosine 2A receptor on T lymphocytes. Together, inosine and adenosine 2A receptor along with cAMP-PKA induced Th1 cell differentiation in the TME. This mechanism was aided by the increased IL-12Rβ2 and IFN-γ transcription as a response to the phosphorylation of cAMP response element-binding protein (pCREB). In addition, inosine was also involved in macrophage-mediated antibody production [8].

1.2. Enterococcus hirae

Enterococcus is a genus of Gram-positive and facultative anaerobic bacteria. Enterococcus hirae (E. hirae) was found to be a favorable gut bacterium for ICB cancer treatment. Clinically, it was shown to be more abundant in cancer patients with a better response to ICB immunotherapy. In a murine model, the recolonization of E. hirae could reverse the treatment resistance induced by FMT in non-responding patients [9]. E. hirae has been reported to be involved in cyclophosphamide (CTX)’s anticancer effects; also, the translocation of E. hirae from the gut into the lymphoid organs induced the generation of T helper 17 (Th17) cells and immune response against tumor [10][11]. In a further study by Daillere et al., an oral administration of E. hirae restored the efficacy of CTX in antibiotic (ATB)-treated-sarcoma-bearing mice by increasing the intra-tumoral CD8/Treg ratio [12]. In addition, E. hirae induced CD4+ Th1 cell responses accompanied with a longer progression-free survival (PFS) in advanced lung and ovarian cancer patients treated with chemo-immunotherapy [12]. This is most likely because E. hirae produced antigens possessing similar epitopes in structure with TAA in cancer patients [13]. Recently, the underlying molecular mechanisms were further investigated, wherein a multifaceted mode was defined by which E. hirae affected antitumor immunity and enabled anticancer effects of CTX, including inducing IFNγ-producing and CD137-expressing effector memory T cell responses, increasing the local delivery of polyamines, and enriching Bifidobacteria in the host [14].
Clinically, both circulating and liver/tumor-infiltrating E. hirae-reactive CD8+ T cell responses were observed only in HBV-related hepatocellular carcinoma (HCC) patients but not in healthy individuals, and the frequency of these cells was positively corelated with the PFS time of the HCC patients. Mechanistically, the E. hirae-associated immune response may suppress the induction of Foxp3+ regulatory T cells and PD-1+ CD8+ T cells [15].
E. hirae was also recently reported to play a role in the antitumor effect of T-cell immunoglobulin and mucin domain-3 (Tim-3) blockade—Tim-3 is an immune check point protein [16]. The oral gavage of E. hirae restored the antitumor efficacy of Tim-3 blockade, which had previously been attenuated by an antibiotic treatment in the preclinical cancer model.

1.3. Ruminococcaceae (Oscillospiraceae) Family

Ruminococcaceae is a family of strictly anaerobic bacteria that are normally present in the colonic mucosal biofilm of healthy individuals [17]. In a study by Panebianco et al. employing a pancreatic ductal adenocarcinoma (PDAC) mouse model, a significant reduction of tumor volume mediated by gemcitabine therapy was related to a reduced proportion of Ruminococcaceae from 39 to 17% [18]. However, more studies demonstrated that Ruminococcaceae may play a favorable role in the response to immunotherapy. One study analyzed the stool samples from 38 patients with solid tumors treated with anti-PD1, wherein a significant increase in Ruminococcaceae was observed in the stool samples from patients who responded to the treatment [19]. Similarly, in another investigation, when applying a FMT from stool samples enriched with Lachnospiraceae, Ruminococcaceae, and Veillonellaceae to nivolumab (anti-PD1 antibodies)-refractory patients, a tumor suppression response was detected in certain partial patients [20]. Furthermore, in a study examining the microbiota of patients with metastatic melanoma who were treated with anti-PD1 immunotherapy, researchers found that the patients responsive to the treatment had a greater relative abundance of Ruminococcaceae, in addition to other species, when compared to that in the non-responsive patients [21]. Mechanistically, the analysis of the systemic immune response demonstrated that the patients with a higher abundance of Ruminococcaceae in their guts had a higher frequency of effector CD4+ and CD8+ T cells in circulation and a preserved cytokine production ability [22].

1.4. Faecalibacterium spp.

Faecalibacterium is a Gram-positive, anaerobic genus of bacteria belonging to the Ruminococaccaceae family. It is featured as one of the main species of bacteria in the gut producing short-chain fatty acids (SCFA) through dietary fiber fermentation. Faecalibacterium spp. were implicated in a variety of studies focusing on the relationship between the gut microbiota and cancer [22]. In the study mentioned above [21], the patients with metastatic melanoma responding to anti-PD1 antibodies (anti-PD1 Abs) had a higher relative abundance of Faecalibacterium compared to that in non-responsive patients. The responders also had a longer PFS accompanied by greater effector CD8+ T cells tumor infiltration. This entry concluded that the abundance of Faecalibacterium in the fecal microbiota is a strong microbial predictor for a clinical response to anti-PD1 therapy, along with the alpha diversity and the abundance of Bacteroidales [21]. In another clinical study, 26 melanoma patients who received anti-CTLA4 Abs treatment were investigated; consequently, Faecalibacterium spp. presented in a higher proportion in patients who had a better response to the treatment and the longer PFS and overall survival (OS). Analysis of the fecal microbiota of metastatic melanoma patients receiving ipilimumab (anti-CTLA4 Abs) revealed that the enriched Faecalibacterium were associated with a longer survival, but also an increased occurrence of ipilimumab-induced colitis [23].
Faecalibacterium prausnitzii (F. prausnitzii) is a key butyrate producer with multifaceted roles in inflammatory responses, as it has been associated with an improved clinical response to the treatment of ICB but also functions to mitigate intestinal inflammation in the context of inflammatory bowel disease [24]. F. prausnitzii is able to produce SCFAs; a recent study revealed that SCFAs actually promoted cellular metabolism, enhanced the memory potential of activated CD8+ T cells, and were required for the optimal recall responses upon antigen re-encounter [25]. Gopalakrishnan et al. reported an enrichment of Faecalibacterium spp. in fecal samples from melanoma patients responding to PD-1 blockade [21]. The study by Peters et al. revealed that the presence of Faecalibacterium spp. in pre-treatment stool samples was correlated with a longer PFS of melanoma patients receiving immunotherapy [26]. Another clinical investigation by Botticelli et al. demonstrated in NSCLC patients treated with nivolumab that Faecalibacterium was more abundant in the feces of responders than that in the non-responders [27].

1.5. Oscillibacter spp.

Oscillibacter is a genus of Gram-negative and anaerobic bacteria belonging to the Ruminococcaceae family. A preclinical study analyzing the effects of gut microbiota modulation on HCC growth revealed that tumor growth was significantly suppressed when the model mice were fed with a diet of “Prohep”, a probiotic mixture. In addition, the tumor suppression was accompanied by altered angiogenesis and antitumor immune responses. The analysis of gut microbiota profiles identified the significant enrichment of several gut microbiota species including Oscillibacter spp. in treated mice. In a gut microbiota analysis of patients with gastric cancer and gastrointestinal stromal tumors (GIST), a lower abundance of Oscillibacter together with Lactobacillaceae were observed in cancer patients compared to healthy controls [28]. Controversially, another clinical investigation revealed that patients with colorectal cancer (CRC) presented an increased mucosal microbiota abundance of Oscillibacter together with Bacteroides, Roseburia, and Ruminococcus. However, no mechanistic study was mentioned; thus, the finding needs further verification [29][30].

1.6. Burkholderia spp.

Burkholderia is a genus of Gram-negative and obligately aerobic gut bacteria. It has been reported that the recolonization of Burkholderia spp. in antibiotically treated mice or germ-free (GF) mice could restore anti-CTLA4 Abs’ therapeutic effect against metastatic melanoma. In this investigation, the researchers observed that a diversified gut microbiota and Burkholderia specifically were required for anti-CTLA4-mediated antitumor effects, in which using antibiotically treated mice or GF mice could abolish the antitumor response to CTLA4 blockade [31]. In addition, Burkholderia pseudomallei was used for a modified carrier of an antitumor vaccine because of its size, shape, and inherent expression of pathogen-associated molecular patterns and invasion-assistant adhesion proteins. Engineered Burkholderia pseudomallei loaded with tumor lysates and CpG enhanced DC maturation and TAA cross-presentation, thereby inducing cellular and humoral antitumor responses and suppressing tumor growth in tumor models [32].

1.7. Prevotella spp.

Prevotella is a genus of Gram-negative anaerobic gut bacteria. Prevotella copri was studied for its correlation with rheumatoid arthritis. Recently, it was found to be related to the therapeutic effect of immunotherapy against NSCLC. The clinical data demonstrate that together with two other bacteria, Prevotella copri was enriched in patients who responded to anti-PD1 treatment accompanied with higher levels of memory CD8+ T cells and NKT cells in the blood [5].
Recently, the contribution of the gut microbiota to castration-resistant prostate cancer (CRPC) was studied. The defined gut microbiota facilitated castration resistance in mice, and these bacteria in mice and patients with CRPC were associated with the function of converting androgen precursors into active androgens. An FMT from hormone-sensitive prostate cancer patients and a Prevotella stercorea administration suppressed tumor progression [33].

3. Bacteria Species Associated with Unfavorable Modulation in Antitumor Immunity

2.1. Fusobacterium nucleatum

Fusobacterium nucleatum (F. nucleatum) is a Gram-negative anaerobic bacillus that has reservoirs in the human mouth, gastrointestinal tract, and other areas. F. nucleatum is a well-known pathogenic bacterium [34][35] that has often been isolated from different types of infectious samples collected from patients. The once understudied bacterial strain has proven to be not just opportunistically infectious but also a contributor to tumorigenesis [36]. It has been implicated in various types of cancer, including colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma, pancreatic cancer, and hepatocellular carcinoma [37].
In multiple studies of CRC, Fusobacterium strains have been detected as a potential biomarker for CRC. In addition, the data demonstrated that the presence of F. nucleatum in CRC cells was not stage-dependent; it could be potentially detected in cancer cells from stage 0 to IV [38]. In a clinical study of CRC patients, F. nucleatum promoted chemoresistance in an oxaliplatin treatment through the activation of the innate immune system [39]. In another study by Flanagan, enriched F. nucleatum was observed in stool samples from CRC patients compared to healthy controls [40]. In addition, Mima et al. observed that the enrichment of F. nucleatum was associated with worse clinical outcomes in CRC patients [41]. F. nucleatum was reported to promote tumor development by inducing inflammation through activation of tumor-associated neutrophils / M2 macrophages and inhibition of cytotoxicity of T and NK cells that repressed the host immune responses [42]. In fact, Fusobacterium aids tumorigenesis through multiple pathways. The surface protein FadA on F. nucleatum binds to E-cadherin presented on CRC and non-CRC cells, stimulating β-catenin signaling and thus causing inflammation and oncogenicity in the cells. Normal E-cadherin functions to suppress tumors by attaching cells together and reducing motility. However, after binding with FadA, E-cadherin loses its function, and the tumor cells grow and metastasize. This also allows F. nucleatum to enter the epithelial and CRC cells, and with the aid of its ability to feed on glucose and amino acids, F. nucleatum survives in the cells without challenges regarding nutrient sources. In addition, F. nucleatum biofilms have been seen in CRC cells due to the adhesive nature of F. nucleatum, which can successfully form biofilms while carrying out the respiration process in hypo-toxic situations. Furthermore, an autophagy mechanism was activated by F. nucleatum that could promote cancer cell survival and potentially induced chemoresistance [39][43][44]. Moreover, F. nucleatum has also been associated with D-galactose-β (1–3)-N-acetyl-D-galactosamine (Gal-GalNAc) overexpression in cancerous cells. A study has shown that the Fap2 protein on F. nucleatum can bind to Gal-GalNAc, which contributes to the increased number of F. nucleatum in CRC, thereby supporting further tumorigenesis [45]. The T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a receptor presented on T and NK cells. The inhibition of the TIGIT can suppress NK cell cytotoxicity. The Fap2 protein also functions to bind to the TIGIT to inhibit NK cell-induced cytotoxicity, aiding cancer cells to survive from immune attack [46]. All the above suggests that the abundance of F. nucleatum might be an early marker of CRC. In addition, antibiotics targeting F. nucleatum could be a safeguard for people with potential risk of CRC.

2.2. Escherichia coli

Escherichia coli (E. coli) is a Gram-negative and facultative anaerobic gut bacteria species belonging to class Gammaproteobacteria. Most E. coli are harmless to the host, but some serotypes may cause poisoning. It has been illustrated that Gammaproteobacteria can hinder the effects of chemotherapy on the tumors. For instance, Gemcitabine (2′,2′-difluorodeoxycytidine), a chemotherapeutic drug, is used to treat patients with pancreatic, lung, breast, or bladder cancers, but Gammaproteobacteria strains that produce the bacterial enzyme cytidine deaminase (CDDL) can significantly metabolize the gemcitabine to its inactive form, 2′,2′-difluorodeoxyuridine, to trigger drug resistance. To establish this, a study compared tumor cells treated with an E. coli strain that expressed CDDL or with a CDDL-deficient E. coli strain. The results confirmed the role of the CDDL-expressing E. coli in inducing resistance to gemcitabine [47].
Additionally, the E coli strain has a gene called “pks” coding genotoxin colibactin, a polyketide-peptide that causes DNA damage. A study has illustrated that even at low doses, live pks+ E. coli induced short-lived DNA damage that contributed to the anaphase bridges and chromosome abnormalities caused by insufficient DNA repair mechanisms. Colibactin or colibactin-producing bacteria alter the TME so as to encourage the formation of senescent cells, which help with tumor promotion and cancer progression via the production of growth factors. To clarify, investigators introduced pks+ and pks E. coli into intestinal cells, and the cells infected with pks+ had an increased number of growth factors stimulating tumor growth. In short, pks+ E. coli cells had an increased level of senescence-associated β-galactosidase (SA-β-gal) activity that induced the senescence of intestinal epithelial cells, which produced growth factors that contributed to tumor growth. E coli downregulated the expression of SENP1, a protein that regulates the sumoylation pathway. The sumoylation of cells has been known to contribute to cell senescence. Upon studying the effect of pks+/− E. coli in colorectal tumors, it was established that the tumor cells and TME had an increased number of hepatocyte growth factor (HGF) mRNAs, activated HGF receptor, some senescence markers such as SA-β-gal and p21cip, and a reduction in the number of SENP1-expressing cells. This result supports the finding that pks gene-containing E. coli assists in tumorigenesis asserted in previous studies [48][49].
Furthermore, in a clinical investigation, researchers observed that E. coli were more abundant in patients with melanoma who did not respond to anti-PD1 treatment than in patients who responded well to the treatment. In addition, the patients with more E. coli had a shorter PFS accompanied with a higher degree of tumor infiltration of Treg cells [21].

2.3. Ruminococcus spp.

Ruminococcus is a genus of Gram-positive anaerobic bacteria recently found in the human gut that belongs to Ruminococcaceae family. The study by Matson et al. involving 42 metastatic melanoma patients receiving a treatment of PD-1 blockade demonstrated that Ruminococcus obeum were over-presented within the microbiota of the poor responders [4]. In addition, in NSCLC patients, Botticelli et al. reported that Ruminococcus bromii were less presented in the responders treated by nivolumab [27]. Recently, a study with 27 metastatic melanoma patients receiving immunotherapy revealed that the reduced survival probably was related to the over-presented Ruminococcus gnavus [26]. In another clinical study in China, the gut microbiota profiles from patients with NSCLC receiving anti-PD1 Abs treatment were analyzed; the results demonstrated that Ruminococcus spp. were mainly found in non-responding patients. However, the defined correlation and mechanisms behind this observation require further investigation [5].

2.4. Gammaproteobacteria Class

Gammaproteobacteria, mentioned above, is a large class of bacteria that has been implicated in the regulation of the therapeutic efficacy of some anticancer drugs. A study employing a colon cancer mouse model observed that the chemotherapy drug gemcitabine was converted into its inactive form by the bacterial enzyme cytidine deaminase, an enzyme seen primarily in Gammaproteobacteria [47]. Therefore, gemcitabine resistance was induced by intratumor Gammaproteobacteria and ameliorated by antibiotic treatment. As gemcitabine is often used for the treatment of PDAC, the researchers found an increased level of Gammaproteobacteria in the pancreatic tumors compared to the normal pancreatic tissues and culturing the bacteria from fresh PDAC tumors with human colon carcinoma cell lines rendered the cell lines fully resistant to gemcitabine. These results led the researchers to hypothesize that the presence of Gammaproteobacteria was a key factor in the metabolism of gemcitabine and a possible target for tumors’ sensitization to gemcitabine treatment. However, it is still unclear whether Gammaproteobacteria can impact antitumor immunity in PDAC patients treated with gemcitabine.

This entry is adapted from the peer-reviewed paper 10.3390/cells11223684


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