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Hypoxia in Cancer Progression: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Rosa Angélica Castillo-Rodríguez.

A clear association between hypoxia and cancer has heretofore been established; however, it has not been completely developed. In this sense, the understanding of the tumoral microenvironment is critical to dissect the complexity of cancer, including the reduction in oxygen distribution inside the tumoral mass, defined as tumoral hypoxia. Moreover, hypoxia not only influences the tumoral cells but also the surrounding cells, including those related to the inflammatory processes.

  • hypoxia
  • Macrophages
  • Fibroblasts

1. Introduction: Hypoxia and Inflammation as a Cancer Hallmark

Chronic inflammation and viral infections often precede the development of cancer. In fact, the association between cancer and inflammation has been reported frequently; as examples, weit can be mentioned ulcerative colitis and colorectal cancer; hepatitis B or C and hepatocellular carcinoma (HCC); tobacco consumption and lung cancer; and human papillomavirus infection and cervical cancer, among many other cases [1,2,3,4][1][2][3][4]. Therefore, a clear connection has been established, implicating that inflammation as immune response promotes oncogenic transformation or supports tumoral progression. Moreover, the cells that coordinate the inflammatory response are responsible for the recognition and elimination of tumoral cells, which develop mechanisms to avoid these processes.
In this complex context, tTumoral hypoxia plays an important role in the regulation of the metabolism and the elements that integrate the tumoral microenvironment (TME). The cellular components of the TME include cancer cells as well as immune cells like lymphocytes T and B, tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), natural killer (NK) cells, Myeloid-Derived Suppressor Cells (MDSCs), tumor-associated neutrophils (TANs), dendritic cells, mast cells, granulocytes as well as adipocytes, endothelial cells and pericytes [5,6][5][6]. An intricate communication is established between cancer and its surrounding cells, releasing several cytokines and molecules to modulate the environment and allow tumoral growth and metastasis. Furthermore, tumoral progression requires extra support of oxygen and energy. In these circumstances, the tumor develops hypoxia, a stressful factor that modifies the phenotype of the cancerous and surrounding cells in order to allow their adaptation and survival. The interconnection between hypoxia and inflammation has been recognized and plays different roles at several levels of the progression of cancer.

2. Macrophages

Immune cells as macrophages and neutrophils are attracted to zones with low levels of oxygen, such as wounds, but also to hypoxic tumoral regions. The presence of macrophages is a well-characterized phenomenon that is associated with cancer, and there has been much study of the presence of the macrophages and the correlation with a bad prognosis [211][7]. Monocytes are recruited to the tumor by chemokines such as CCL2, CCL5, CCL7, CCL8, CXCL12, VEGF, and M-CSF, and become TAMs [154,212][8][9]. TAMs release cytokines such as IL-8 or TGF-β and pro-angiogenic factors such as VEGF and FGF2, which induce revascularization to bring nutrients to the zones without irrigation, allowing tumoral progression. In addition, the intercommunication between tumoral cells promotes the release of endothelin-1 and endothelin-2 and induces the secretion of MMP2, MMP7, or MMP9, increasing the metastasis. In addition, TAMs generate an immuno-protective environment, inhibiting the activation of T cells [158][10]. In addition to the presence of macrophages in the tumor, the subtype of the macrophage is also crucial. Macrophages have a specific subtype, named M1 or M2. The M1 phenotype is activated in the presence of microorganisms or IFN-γ and is characterized by high secretion of IL12/IL-23 but low IL-10. M1 cells have an inflammatory profile and eliminate pathogens and debris and therefore are considered as a tumor suppressor phenotype. In this sense, the M1 phenotype releases IL-12, IFN-γ, TNF-α, IL-1β, ROS, and nitric acid, hence promoting the recruitment and activity of NK cells and CD8 + T cells in the tumor microenvironment to induce an anti-tumor immune function and inflammation. Furthermore, IL-1β, TNF-α, and IL-1 activate NF-κB through binding to their corresponding receptors [213][11]. On the contrary, the M2 phenotype is related to an anti-inflammatory function, linked to the release of proliferative signals and the revascularization of the tumor. Importantly, the tumoral cells release cytokines that induce the polarization of the TAMs to the M2 phenotype [154,214][8][12]. In this sense, the M2 phenotype is induced by signals such as IL4, IL10, IL-13, TGF, M-CSF, and glucocorticoids, among other cytokines. Activated M2 macrophages produce high levels of IL-10, IL-6, and EGF, which activate the JAK/STAT3 signaling. Moreover, M2 macrophages release CCL22, but in contrast to the M1 phenotype, produce low levels of IL-12 [213,215][11][13]. CCL22 promotes the infiltration of Treg cells to the tumor, releasing IL-10, which suppresses the antigen presentation function of dendritic cells and the anti-cancer response of CD8+ T cells [213][11]. On the other hand, studies have reported the overexpression of PD-L1 in M2 macrophages, which binds to CD8+ T cells through the programmed death-1 (PD-1) receptor, thereby achieving the tumor immune escape [213][11]. However, it is worth noting that there is a combinatorial spectrum of macrophage populations, other particular populations, such as CD169+ macrophages and TCR+ macrophages, have been recognized. Moreover, some groups reassign tumor-associated macrophages as a particular population with a potential switch from the M1 to M2 profile and vice versa, which can be used as a therapeutic approach [216][14]. In this context, tThe hypoxic microenvironment induces the M2 phenotype, promoting the survival of tumoral cells. In addition, the low concentration of oxygen modulates the expression of hypoxia-sensitive genes in M2 TAMs, particularly those related to angiogenesis [159][15]. For example, M2 TAMs secrete IL-6 with the corresponding expression of the IL-6 receptor in the tumoral cells, activating the STAT3 pathway to promote survival in the tumoral cells located in the hypoxic region [162][16]. Moreover, in a hepatocarcinoma model, hypoxia, as well as the necrotic debris of tumoral cells, induced IL-1β release from M2 TAMs, which up-regulated the expression of HIF-1α through the NF-κB/COX-2 pathway. Interestingly, this profile induces a mesenchymal phenotype in the tumoral cells, characterized by an increment of vimentin and a reduction of E-cadherin [66][17]. However, even the induction of M2 TAM phenotype by hypoxia is clear; in some cases a pro-inflammatory profile has also been reported [66,163,217][17][18][19]. Importantly, HIF is a key regulator in the bidirectional response between the macrophages and the tumoral cell; therefore, the presence of macrophages in hypoxic conditions has been linked to a bad prognosis. The hypoxic microenvironment, through HIF as the principal mediator, induces the secretion of chemokines, which recruit macrophages and restrain them in the tumor. For example, HIF induces the expression of CCL2 in pancreatic ductal adenocarcinoma cells, which induces the recruitment of macrophages to the tumor [155][20]. Other chemokines related to monocyte recruitment in hypoxia are CCL5, VEGF, EMAP II, and endothelin-1 and 2 [156][21]. It has been reported that hypoxia, through HIF-1α, induces the up-regulation of CXCR4 in TAMs but also in endothelial and cancer cells; this axis regulates the migration of the different cells that integrate the TME [157][22]. In addition, hypoxic macrophages show elevated secretion of CCL4 and promote MMP9 expression in glioblastoma cells, while the hypoxia up-regulates the CCR5 expression [161][23]. Even more, there is also a clear effect between the recruitment and activation of the tumoral macrophages and the presence of HIF. It seems that HIF benefits the recruitment and the M2 phenotype polarization. For example, the induction of HIF-1α leads to IL-10 expression and, as a consequence, the polarization of M2 macrophages in an inflammatory environment due to obesity [164][24]. Furthermore, it seems that hypoxia through HIF is a major regulator of the M2 polarization in macrophages, although in some cases it seems that HIF could support the M1 phenotype and also be protective [167][25]. Recently, it has been reported that hypoxia can contribute to immune evasion avoiding macrophage phagocytosis through the regulation of CD47 expression in cancer cells. CD47 is a cell-surface protein that binds to the signal regulatory protein α (SIRPα) expressed in macrophages, preventing phagocytosis. Moreover, HIF-1α activates the transcription of CD47 in breast cancer cells in hypoxia [218][26]. As a consequence, anti-CD47 antibodies have been proposed as therapeutic alternatives, with favorable results [219][27]. Macrophages can also recognize and eliminate tumoral targeted cells marked with antibodies, in a mechanism known as antibody-dependent cellular phagocytosis (ADCP). Fcγ receptors expressed in macrophages recognize and bind to the Fc regions of antibodies, activating a signaling cascade, resulting in phagocytosis being proposed as a possible strategy for immunotherapies [220][28]. However, ADCP is impaired by the inhibitory receptor FcγRIIb. Interestingly, HIF-1α induced the transcription of FcγRIIb, contributing to the resistance to immunotherapy in hypoxic tumors [221][29]. Delprat and colleagues make a distinction and propose that intermittent hypoxia, also known as cycling hypoxia (cyH), exacerbates the inflammatory response in the TME. In particular, cyH induces a pro-inflammatory phenotype in unpolarized M0 and amplifies this profile in M1 macrophages through the activation of the c-jun/p65 signaling pathway [222][30]. Even though the principal and best-characterized mediator of hypoxia is HIF-1α, some evidence suggests that HIF-2α also has an important role in the modulation of the macrophage function. Mice with myeloid cells lacking HIF-2α expression show a diminution in the infiltration of TAMs, apparently through the modulation of the expression of M-CSF receptor and CXCR4, hence reducing the tumoral progression [223][31]. It seems that the different isoforms of HIF could be induced from a different stimulus. For example, Th1 cytokines benefit the M1 phenotype through HIF-1α, whereas Th2 induces the M2 phenotype through HIF-2α and regulates the NO production [224][32]. Moreover, the activating transcription factor (ATF4) is stimulated by stress signals, including hypoxia [225][33]. In this sense, macrophages in hypoxic conditions express not only HIF-1α and HIF-2α, but also ATF4 [226,227][34][35]; more importantly, ATF4 is capable of inducing the recruitment of M2 macrophages to the tumor in a hemangioma model [228][36]. Tumoral hypoxia produces metabolic modifications, including the activation of the glycolytic pathway, the inhibition of oxidative phosphorylation (OXPHOS) in mitochondria, and the accumulation of lactate. HIF-1α is a major inductor of glycolysis, which allows M1 macrophage differentiation. Furthermore, OXPHOS and glycolysis are required for M2 macrophage differentiation. The regulation of this switch would participate in the anti-tumoral protection [165][37]. On the other hand, lactosis in solid tumors is related to the differentiation of monocytes to macrophages. Moreover, TAMs exhibit an inflammatory profile, such as CXCL1, CCL18, and CCL24, which favor the accumulation of immunosuppressive myeloid cells, T cells, and monocytes, as well as M-CSF, which induces monocyte recruitment and M2 TAM differentiation, conferring a protumor and inflammatory M2 phenotype [163][18]. The effects of angiogenesis induced by the TAMs go beyond the release of angiogenic factors. Recently, it has been reported that macrophages themselves could form non-endothelial vascularity around the tumor, derived from the hypoxic stimulus [160][38]. This flexibility is evidence of the multiplicity of the tumoral environment to facilitate tumoral progression. The regulation of the TME is related also to different levels, including miRNAs. These non-coding RNAs regulate different functions in the cell, and it seems that they are involved in the regulation of the immune cells that surround the TME; miRNAs have been extensively reviewed elsewhere [150][39]. A recent example is miR-155 and miR-21, which regulate the TAM function and reduce tumoral growth [229][40]. Interestingly, miR-17 and miR-20a regulate the expression of HIF2-α, even in normoxic conditions, and induce a pro-angiogenic response in TAMs [230][41]. In another example, hypoxia induces the expression and secretion of miR-940 in exosomes of epithelial ovarian cancer, which are delivered in macrophages and lead to M2 polarization and thus cancer progression [166][42].

3. Fibroblasts

The fibroblasts are the most abundant cell type in the stroma and usually secrete extracellular matrix in wounds to achieve reparation, following the evolution in the inflammation process. However, in the complexity of the TME, the CAFs acquire a pro-tumoral function, including the induction of metastasis through the remodeling of the extracellular matrix (ECM) and the secretion of angiogenic and proliferative factors [231][43]. In this sense, tumor cells induce the transformation of stromal fibroblasts into pro-tumorigenic CAFs through the release of IL-6, TGFβ, PDGF, exosomes, and specific TME stimulus, including hypoxia, acidification, and oxidative stress, which promote the recruitment and activation of fibroblasts [168,169,232][44][45][46]. It has been demonstrated that tumoral cells induce the transformation of fibroblasts isolated from an initial hyperplastic state into CAFs with pro-inflammatory properties. CAFs, through the IL-1β/NF-κB signaling axis, induce the transcription of COX-2, IL-1β, IL-6, CCL3, CXCL1, CXCL2, CXCL5, MMP3, and MMP12, leading to macrophage recruitment, angiogenesis, tumoral growth, and metastasis [233][47]. In addition, the treatment of fibroblasts with pro-inflammatory leukemia inhibitory factor (LIF) induces an epigenetic switch, through p300 histone acetyltransferases that acetylate STAT3. Then, STAT3 induces the transcription and activation of DNMT3b methyltransferase, which inhibits the tyrosine phosphatase (SHP-1) expression, resulting in constitutive activation of the JAK1/STAT3 pathway and leading to extracellular matrix remodeling and collective migration and invasion of neoplastic cells [234][48]. Moreover, CAFs impair tumor immunity due to the induction of massive infiltration of myeloid cells into the tumor stroma. CAFs also decrease the proliferation and activation of T cell cytotoxicity [235,236][49][50]. However, as previously mentioned, hypoxia and oxidative stress induce the differentiation of CAFs and lead to metastasis. In this regard, ROS induces the conversion of stromal fibroblasts into migrating myofibroblasts, due to the accumulation of HIF-1α, which promotes the activation of the CXCL12/CXCR4/Rho A signaling pathway. These characteristics were found in HER2-human breast carcinomas, which present high rates of cell proliferation, neovascularization, and metastasis [170][51]. Another approach showed that breast cancer cells lead to the transformation of fibroblasts to CAFs through an autophagic mechanism. Tumoral hypoxia activates HIF-1α and NF-κB transcription factors, which drive the autophagic degradation and loss of Cav-1 with the consequent stabilization of CAFs, thus exerting pro-tumoral actions that will benefit the metastasis of the cancerous cells [171][52]. In this regard, CAFs play an important role in the regulation of cancer metabolism, primarily through the secretion of metabolites and the generation of a stiffer and fibrotic ECM, which in turn affects cancer cell metabolism. In this sense, it has been proposed that the activation of catabolic and autophagic pathways in CAFs increase the production of metabolites such as pyruvate, lactate, glutamate, and ketone bodies that are available to the surrounding cancer cells; moreover, this correlates with a higher invasive and resistance capacity of these cells through a reciprocal metabolic reprogramming [235,237][49][53]. However, the effects of hypoxia on CAFs could seem contradictory. For example, the hypoxic conditions seem to reverse the pro-tumoral phenotype of the CAFs, observed with the impairment of the ECM remodeling and CAF-induced cell invasion, through a mechanism dependent on the inhibition of PHD2 through low oxygen levels and the consequent stabilization of HIF-1α in a breast cancer model, making PHD2 in CAFs a probable therapeutic target [172,173][54][55].

4. Natural Killer Cells

NK cells are lymphocytes from the innate response associated to antitumor protection [238,239,240][56][57][58]. In this sense, activated NK cells recognize and eliminate tumoral cells without the requirement of previous recognition. For instance, NK cells recruit type 1 dendritic cells to the tumor and promote T1 cell polarization through the release of CCL2, CCL3, CCL4, CCL5, XCL1, and CXCL8, thus inducing anti-tumoral protection [241,242][59][60]. NK cells also release granules with cytotoxic content, such as IFN, TRAIL, and FasL. NK cell-through killing is executed by FASL and TRAIL on the NK cell surface, which leads to apoptotic cell death in target cells. Furthermore, the NK cells contain lytic granules with perforin, a protein that causes membrane pores, and granzymes, a family of serine proteases, which are exocytosed to lysed target cells [243][61]. These properties seem very beneficial to developing new cancer immunotherapies [239][57]. Cellular acidity derived from anaerobic metabolism due to hypoxia has detrimental effects on NK and T cells [174][62]. In this sense, the TME facilitates the tumor evasion of the immune system. As the tumor grows and hypoxia is established, cancer cells change their metabolism to a glycolytic profile; in this contCext, cells metabolize pyruvate to lactate through LDH, inducing an acidic environment. The high levels of lactate and pyruvate induce the accumulation of HIF-1α, even in the presence of oxygen, and as a consequence induce the expression of genes from the HIF-1α pathway, including those that lead to a glycolytic environment [244][63]. Moreover, LDHA, a target of HIF-1α [245][64], leads to lactate accumulation, which in turn impairs the function of NK cells and T lymphocytes [175][65]. High levels of lactate inhibit the production of IFN-γ, apparently through the inactivation of the nuclear factor of activated T cells (NFAT). A diminution in the viability of both NK cells and T lymphocytes was detected in this lactic environment [176][66]. Moreover, evidence shows that the accumulation of lactate and this acidic environment impairs the cytotoxicity action of NK cells, which is favorable to tumoral cell proliferation and protection from the immune system [175,177][65][67]. As previously discussed, hypoxia has a crosslink with the STAT pathway. It has been reported that hypoxia induces impairment of the NK cell cytotoxicity against tumor cells, and this effect is associated with the reduction in the phosphorylation of ERK and STAT3. The ERK and STA3 phosphorylation depend on the activation of the tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1 (SHP-1) by hypoxia; in fact, the pharmacological inhibition of SHP-1 by TPI-1 allows a partial recuperation of NK cytototoxicity [246][68]. NK cells express the NKG2D transmembrane receptor that binds to their ligand (NKG2DL), present in the tumor cells; thus, NK cells can recognize and kill the tumoral cells [247][69]. However, the microenvironment may modify the expression of NKG2D receptor or ligand, avoiding tumoral immunosurveillance. For example, in a model of resistant prostate cancer, hypoxia decreased the expression of UL16 binding protein, which is a member of the NKG2D family, and MHC class I chain-related proteins A and B (MICA/MICB). Apparently, hypoxia also induced the expression of PD-L1, which could be blocked with inhibitors of the JAK/STAT3 axis to re-activate the cytotoxic action of NK cells [178][70]. In accordance with this, another group reported a decrease in MICA expression in osteosarcoma cells, inhibiting the NK cell antitumoral cytotoxicity [181][71]. In a model of pancreatic cancer, Ou and colleagues found that hypoxia leads to a significant presence of soluble major histocompatibility complex class I, chain-related (sMICA), related to the shedding of membrane MIC (mMICA) from the tumor cell membrane to a soluble form. In addition, the expression of NKG2D was downregulated, avoiding the NK cytotoxicity over tumoral cells [179,180][72][73]. Alternatively, the shedding of sMICA could be inhibited by nitric oxide signaling, counteracting the hypoxic effect [248][74]. Moreover, the participation of dysregulated circRNAs and miRNAs such as circ_0000977/miR-153 was linked to the regulation of HIF-1α. In hypoxia, an increase in the presence of circ_0000977 was detected and correlated with an upregulation of HIF-1α, while miR-153 had the opposite action. More interesting, miR-153 was able to bind to circ_0000977 and HIF-1α, establishing a possible mechanism of regulation. The reseauthorchers proposed that hypoxia leads to an increase of circ_0000977, which inhibits miR153 and releases its repression over HIF-1α and A Disintegrin and Metalloproteinase Domain 10 (ADAM10). Then, a transition from membranal MICA to soluble MICA occurs; sMICA then bounds to NKG2D over NK cells, decreasing their stimulation and leading to the immune escape of the tumoral cells [180][73]. In contrast, Sarkar and colleagues suggested that the detrimental action of hypoxia over NK cells could be counteracted with a pre-activation of NK cells by IL-2 using a model of melanoma. Apparently, in this model, they did not find alterations in the levels of MICA/B, HLA-ABC, and ULP1-2 under hypoxia [249][75]. Hypoxia decreases the levels of other NK cell membrane receptors, such as NKp46, NKp30, and NKG2D, as previously mentioned. Then, NK cell ability to eliminate tumor cells would be reduced [250][76]. Interestingly, CD16+ NK cells recognize the Fc of immunoglobulins attached to target cells, establishing a mechanism known as antibody-dependent cellular cytotoxicity (ADCC) to eliminate them. Moreover, hypoxia seems not to particularly affect the ADCC mechanism. Solocinski and colleagues used a model with NK cells that overexpress CD16 receptor and showed that these cells maintain their cytotoxic capacities in hypoxic conditions, being a potential strategy for immunotherapy in cancer [251][77]. It has been observed that hypoxia did not decrease the expression of CD16 receptor in NK cells, contrary to other activating receptors [250][76]. Metabolic stress such as in the hypoxic microenvironment is also related to the release of eADO. Hypoxia induces dephosphorylation of adenosine triphosphate (ATP) through nucleoside triphosphate dephosphorylases (NTPD) and upregulates the activity of ectonucleotidases such as CD39 and CD73, increasing the adenosine levels. Then, adenosine modulates immune cells through the activation of adenosine receptors such as A1, A2A, A2B, and A3, located in the immune cells [252][78]. Particularly in NK cells, adenosine seems to inhibit granule exocytosis and the lytic activity of NK cells. An extended review of this topic has been published recently [84]. The TME depends on the intercommunication between the tumoral cells and surrounding cells, and hypoxic signals model this communication in both directions. In a revealing work, Krzywinska and colleagues demonstrated that the deletion of HIF-1α in NK cells impairs their cytotoxicity but decreases tumoral growth [182][79]. Moreover, the NK cells with HIF-1α deletion were associated with a deficient vasculature in the tumors and consequently with metastasis. The absence of HIF-1α in NK cells was associated with a decreased expression of the soluble form of VEGF receptor 1 (sVEGFR1) in the tumors from mice with NK cells with HIF-1α deletion. Interestingly, sVEGFR1 sequestrates VEGF and modulates its bioavailability. In this case, the secretion of HIF-1α from NK cells leads to the expression of sVEGFR1 and avoids aberrant angiogenesis in tumors through the regulation of bioavailability of VEGF [182][79].

5. Myeloid-Derived Suppressor Cells

The MDSCs are immature myeloid cells that originated in bone marrow from immature myeloid cells (IMCs) and differentiate in dendritic cells, macrophages, and granulocytes. MDSCs are characterized by their suppressive activity over T cells; moreover, MDSCs have been associated with the inhibition of antitumoral immunity and the promotion of tumor progression [190,253,254][80][81][82]. This response is related to the release of pro-angiogenic molecules, including VEGF-A, Bv8, bFGF, elastase, and MMP9 [255,256][83][84]. The MDSC are classified according to their lineage into two groups: monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs). MDSCs are activated by several stimuli, such as tissular damage, pathogens, chronic infections, autoimmune diseases, and inflammatory signals in the context of cancer [254][82]. MDSCs are present in the majority of cancer types, promoting the progression of the tumor and inhibiting the antitumoral immunity mediated by T cells; in fact, this represents an obstacle to the immunotherapies against cancer [190,257][80][85]. MDSCs produce high levels of ROS and nitric oxide, which hinder the infiltration, activation, and apoptosis of T cells [255,258,259][83][86][87]. MDSCs also produce ROS and peroxynitrite, which induce the nitration of CTR/CD8 receptors, reducing their interaction to cognate antigen-MHC complexes and thus inhibiting CD8+ T cells [258][86]. Tumors release prostaglandin E2 (PGE2), inducing the nuclear accumulation of p50 NF-κB in M-MDSCs. Furthermore, p50 facilitates the binding of STAT1 to DNA to activate the transcription of nitric oxide synthase (NOS2) and other genes dependent on IFNγ activation, promoting an immunosuppressive phenotype of MDSCs [260][88]. Furthermore, MDSCs induce the expression of immunosuppressive cytokines and mediators, such as COX2, arginase (Arg) 2, inducible nitric oxide synthase 2 (iNOS2), PD-L1, TGFβ, IL-10, and CCR5, leading to activation and infiltration of Tregs as well as NK cell inhibition [255,259][83][87]. In this context, intratumoral hypoxia induces the expression of immunosuppressor molecules such as CD47 and PD-L, cytokines such as CCL26, and proteins such as ectonucleoside triphosphate diphosphohydrolase 2 (ENTP2/CD39L1), which depend on HIF activity. These molecules act as chemoattractants to recruit and increase the MDSCs in the tumor and to inhibit indirectly the cytotoxicity produced by the NK cells, prevent immune surveillance, and increase tumoral growth and progression [183,184,185][89][90][91]. Moreover, the overexpression of ENTPD2 leads to an increase of AMP, which prevents the differentiation of MDSC and facilitates its accumulation in the tumor [185][91]. In this sense, some growth factors such as VEGF also act as a chemoattractant of MDSC. MDSC secretes VEGF, inducing angiogenesis [184,190,191,192][80][90][92][93]. The overexpression of CD45 protein tyrosine phosphatase (PTP) in MDSCs exposed to hypoxia in the tumor site promotes the inactivation of STAT3, resulting in the M-MDSC differentiation to TAM [188][94]. Moreover, hypoxia induces a shift from the dimeric to the monomeric form of CD45 phosphatase, the more active form of this protein. Apparently, when M-MDSCs migrate to the tumor, the hypoxia induces the overexpression of sialin, a sialic acid transporter, facilitating the transport of sialic acid to the membrane, allowing its binding to CD45 phosphatase and preventing its dimerization. The activation of CD45 phosphatase then leads to inactivation of STAT3, thus facilitating MDSC differentiation into TAM [188][94]. Likewise, it has been described that HIF-1α mediates the differentiation of MDSCs to TAMs through the upregulation of iNOS and Arg1. Consequently, the expression of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 2 and ROS in MDSCs decreases, leading to the suppression of antigen-specific and nonspecific T cell activity [189][95]. In addition, hypoxia can increase the MDSC activities through HIF1α/miR-210 signaling. miR-210 enhances the Arg1 activity and NO levels, without alteration of ROS, IL6, IL10, and PD-L1 levels [261][96]. It has been observed that lactate localized in hypoxic areas induces the recruitment of MDSCs and inactivates NK cells in the tumor site, resulting in a suppression of the anti-tumoral response [175][65]. In fact, it has been demonstrated that lactate derived from tumor cells upregulates the expression of PD-L1 [262][97]. In this sense, an essential mechanism of immunosuppression is mediated by HIF-1α/PD-L1 signaling in TAM, MDSCs, and dendritic cells by hypoxia [186,187][98][99]. In addition, it has been reported that the upregulation of PD-L1 transcript in hypoxia is mediated by the cooperative interaction of PKM2/HIF-1/p300 on the PD-L1 promoter [187][99]. Furthermore, PD-L1 on cancer cells induces the glycolytic process through Akt/mTOR signaling, inducing an immunosuppressive tumor microenvironment [263][100]. The blockade of PD-L1 with a monoclonal antibody in hypoxia reverts the immunosuppressive response, increasing the proliferation and activity of T cells accompanied by the downregulation of IL-6 and IL-10 in MDSCs. Thus, the inhibition of PD-L1 in tumoral hypoxia is proposed as a potential treatment [186][98].

6. T Cells

T cells are also important for adaptative immunity and usually mature in the thymus. Naïve T cells are activated after the interaction of the antigen-T cell receptor to differentiate in CD4+ or CD8+. In the case of CD4+ T cells, they can be divided into helper (Th) and regulatory T cells (Treg). Th cells, in turn, are subdivided into distinct subtypes and activate different cellular types: Th1 releases IFN-γ and IL-2 to activate macrophages and cytotoxic T cells; Th2 secretes IL-4 and IL-13 and activates B cells, while Th17 releases IL-17A to recruit neutrophils and macrophages. Treg suppresses the immune response. CD8+ T cells or cytotoxic T cells release pro-inflammatory cytokines such as INF-γ and TNF-α as well as cytotoxic molecules such as perforin and granzymes and can eliminate cells that are infected. After antigen stimulus, T cells proliferate using aerobic glycolysis, as c-Myc and HIF are important regulators to control glycolysis and glutaminolysis [264][101]. In particular, hypoxia can also affect the functions of T cells, apparently supporting the antitumoral response. Palazon and colleagues demonstrated that HIF-1α induces a glycolytic profile and increases the migration of CD8+ T cells. Moreover, an increase in the cytotoxic activity of CD8+ T cells was observed, linked to the increase of costimulatory molecules such as CD137, OX40, GITR, PD-1, TIM3, and LAG3 and the production of granzyme B. VEGF-A expression, a target gene of the HIF pathway, is also correlated with tumoral vascularization [193][102]. Other groups have reported that hypoxia enhanced the lytic activity and function of cytotoxic T lymphocytes (CTLs), related to the increase of granzyme-B [194,195,196][103][104][105]. On the contrary, another group reported that HIF2α and not HIF1α induces cytotoxic differentiation and cytolytic activity over CD8+T using retroviral vectors for ectopic expression of HIF1α and HIF2α in CD8+ T cells [197][106]. However, there is controversy around hypoxia and its adverse effects in cancer. For example, hypoxia has been linked to radiotherapy resistance. In this sense, hypoxia downregulates the MHC I expression of tumor cells, avoiding their recognition by CD8+ T cells. In addition, hypoxia seems to reduce the levels of CXCL9, CXCL10, and IDO, whose expression is stimulated by IFN-γ, as a potent cytokine with antiproliferative actions [198][107]. Thus, hypoxia reduces the proliferation and antitumor functions of CD8+ T cells, preventing the antitumoral immune response [199][108]. Interestingly, the chronic response of T cells to a prolonged stimulus such as cancer has been defined as T cell exhaustion [265][109]; moreover, the density of exhausted T and B cells, as well as T-cell exhaustion–related genes like PDL1, B7H3, FOXO1, and PRDM1, correlates with a high expression of HIF-1α in glioblastoma [200][110]. HIF-1α and VEGFA promote the differentiation of the CD8+T cells to exhausted T cells, highlighting their proangiogenic profile [201][111]. Recently, a subset of T cells that do not recirculate, known as tissue-resident memory T cells (TRM), was identified. TRM cells express CD69 and CD103 in some tissues and secrete different cytokines according to their residency as TGF-β, IL-15, Type I IFN, and IL-12, contributing antitumoral activity and better prognosis. In this sense, the presence of hypoxia and TGF-β1 induce the differentiation of CD8+ T cells to TRM [202][112]. Moreover, hypoxia promotes the antitumor effect of TRM cells, as was evaluated using a VHL-deficient CD8+ T cell tumoral model [266][113]. It has been reported that a synergism exists between the expression of TGF-β and hypoxia to induce the differentiation of CD8+ T cells in the TRM, which contributes to antitumoral response [267][114]. Moreover, another subset of T cells known as gamma delta (γδ) T cells, found in peripheral blood, has been described as expressing characteristics of innate and adaptive immune responses and has been postulated as a candidate for immunotherapy in cancer [268][115]. Interestingly, hypoxia drives a reduction in γδ T cell cytotoxicity against oral tumoral cells, due to a decrease in the degranulation of the cytotoxic contents and inducing their differentiation to γδT17, which releases IL-17, a pro-tumorigenic cytokine [203][116]. A precondition of anti-angiogenesis therapy in cancer using anti-VEGF antibodies demonstrated improvement of the function of CD8+ T cells, apparently linked to an increase in hypoxia due to the inhibition of VEGFR2 signaling [269][117]. In another immunotherapy model, CTLs were preincubated in 1% oxygen and showed that the package of granzyme-B per granule was more efficient and thus their cytotoxic effect improved. This correlates with a better regression of the tumor in vivo in a model of melanoma [270][118]. Besides the HIF-1α pathway, other signaling pathways can participate and modulate T cell function. For instance, delta-like 1 (DLL1), is a ligand of the Notch pathway that is expressed in endothelial cells and has been linked to aberrant vascularization in cancer, acting as a compensator of tumoral hypoxia. When DLL1 is overexpressed in breast and lung cancer lines, it induces a normal vascularization around the tumor and the activation of CD8+ T cells, which could be useful in cancer immunotherapy, ameliorating the distribution of the antitumoral drugs [271][119]. Moreover, it has been demonstrated that HIF-1α binds to the FoxP3 promoter and induces its expression. FoxP3 is a crucial regulator of T cell differentiation into Treg, which deploys anti-inflammatory mechanisms associated with a bad prognosis in cancer [204,205][120][121]. Recently, the role of HIF-2α in the stabilization of Treg has been characterized. In fact, the knockout of HIF-2α in Treg results in an inability to suppress inflammation; moreover, the implantation of Tregs with the knockout of HIF-2α resulted in a restriction of the tumoral growth in an in vivo model of colon carcinoma [272][122].

7. B Cells

B cells are responsible for the humoral immune response. Briefly, B cells mature in bone marrow, and then they exit to the bloodstream and ganglia, where are exposed and recognize antigens; later, they differentiate into plasmatic or memory cells, both with the capacity to produce antibodies. Normally, B cell development occurs in the bone marrow and implies their maturation and selection through the B cell receptor (BCR). Interestingly, the regulation of HIF-1α is essential for the normal maturation of B cells. A sustained expression of HIF-1α leads to developmental arrest and BCR defects due to suppression of the proapoptotic BCL-2-interacting mediator of cell death (BIM) [273][123]. Additionally, HIF-1α induces a glycolytic profile in immature B cells [274,275][124][125]. Several studies have reported the capacity of B cells to promote an antitumoral function [276,277][126][127]. For instance, B cells enhance T cell antitumoral response by acting as antigen presentation cell (APC), or they release effect cytokines as IFN-γ to polarize T cells towards a Th1 or Th2 phenotype [278][128]. It has been reported that both CD20+ B cells and CD8+ T cells cooperate to induce antitumor immunity in ovarian cancer, increasing patient survival significantly [276][126]. In another example of anti-tumoral response, margin infiltrating B cells mediated direct cytotoxicity through the secretion of IFN-γ, TRAIL, and granzyme B on hepatoma cells [279][129]. Furthermore, human B cells stimulated with CpG-oligodeoxynucleotides showed a tumor-killing effect through TRAIL/Apo-2L signaling [280][130]. The role of hypoxia in B cells in a tumoral context is still under discussion. Lee and colleagues showed that the deletion of HIF-1α induced B cell infiltration and accelerated the progression of pancreatic cancer [206][131]. On the contrary, B regulatory cells are particularly important in cancer, as they exert an immunosuppressive role. B regulatory cells secrete TGFβ and IL-10; in fact, IL-10 suppresses innate immune responses, which results in tumoral protection [281][132]. However, in cancer, hypoxia seems to enhance the IL-10 production by B cells. For instance, hypoxia induces the expression of the high-mobility group B1 (HMGB1) in the tumor cell-released autophagosomes (TRAPs), which in turn induce IL-10 production in B cells, with a consequent suppression of T cell function and thus protection for tumors against immune response [207][133].

8. Endothelial Cells

Diverse stimuli such as proinflammatory cytokines and TNF-α in the circulation activate endothelial cells, increasing their permeability and inducing leukocyte adhesion. Endothelial cells under proinflammatory conditions induce the expression of E-selectin [282][134] and P-selectin overexpression [283][135] to promote the “tethering” and “rolling” of leukocytes through interaction between selectins and their PSGL-1 ligands [284][136]. Endothelial cells also release cytokines such as IL-8, which binds to CXCR1 and CXCR2 on neutrophils [285[137][138],286], and chemokines including CCL2 or MCP-1, which act through CCR4 and CCR2 on T lymphocytes and monocytes [287,288][139][140]. Leukocyte rolling is controlled by the expression of specific adhesion molecules on leukocytes and endothelial cell surfaces. The endothelial cells express the surface integrins ICAM-1 and VCAM-1, leading to the expression, spreading, and clustering of receptors such as VLA-4 and LFA-1 in the leukocytes, mediating the adhesion and transmigration of the leukocytes into the subendothelial spaces of the vessel wall [288,289,290,291,292][140][141][142][143][144]. The mechanisms of adhesion of cancer cells to endothelial cells and the transmigration through the endothelium are still under discussion. Tremblay and colleagues demonstrated that E-selectin induced by IL-1 is necessary for the adhesion and rolling of circulating colon neoplastic cells on endothelial cells and also is required by subsequent diapedesis [293][145]. ThRese authoarchers suggested that colon cancer cells bind at endothelial cells and induce an endothelial cell retraction and blebbing; thus, cancer cells can be engulfed in large vacuoles and transported within and through the endothelial cells [293][145]. In this sense, it has been demonstrated that breast adenocarcinoma MCF-7 cells were able to adhere to endothelial cells and promote their retraction as well as promote the apoptosis of HUVEC, inducing transendothelial migration [294,295][146][147]. In addition, Laferrière and colleagues reported that TNF-α mediated the adhesion between HT-29 colon cancer cells and HUVEC cells via E-selectin upregulation [296][148]. This process promotes the activation of SAPK2/p38/HSP27signaling in HT-29, enhancing mobility and transendothelial migration [282][134]. Furthermore, it has been suggested that tumor cells promote the apoptotic death of endothelial cells and migrate through a cavity formed in an endothelial cell monolayer [297][149]. In addition, it has been proposed that the tumor cell transmigrates through the endothelial cell–cell contacts [297][149]. In this sense, vascular tissues showed that VE-cadherin–containing adherent junctions were relocated and not opened or disrupted, whereas PECAM-1–containing junctions were opened during PMN transendothelial migration [298][150]. The permeability of endothelial cells to circulating tumor cells (CTCs) has a key role in the induction of metastasis, and this characteristic could be affected by hypoxia. Using a model of lung cancer, acute hypoxia leads to the stabilization of HIF-1α, increasing microvascular permeability and allowing the retention of myeloid cells, thus establishing a pro-metastatic environment characterized by a decrease in endothelial cells (CD31+CD45−). The expression of HIF-2α predominates in chronic hypoxia, decreasing the capacity of endothelial cells to permeate to CTC. In hypoxic conditions, the intercellular adhesion molecule 1 (ICAM1), involved in endothelium-macrophage adhesion, and the levels of CCL2, a cytokine that allows the interaction of endothelial cells and macrophages, were elevated, contributing to macrophage recruitment and metastasis. Moreover, myeloid cell infiltration was notably higher [208][151]. On the other hand, Schmedtje and colleagues reported that hypoxia induces the transcription of COX-2 through p65 NF-κB activation in HUVEC cells [299][152]. It has been suggested that prostaglandin and PAF synthesis in endothelial cells by COX-2 and PLA2 induces the adherence of neutrophils to the endothelium after hypoxia [209,300][153][154]. It has also been demonstrated that hypoxia promotes the endothelial ICAM-1 upregulation as well as monocyte–endothelium interaction by HIF1/Arg2/mitochondrial ROS [210][155].

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