Tumor-derived factors affecting immune cells

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Tumor-derived factors affecting immune cells Vincenzo Russoa,* , Maria Pia Prottib,* a Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, San Raffaele Scientific Institute, DIBIT, Via Olgettina 58, 20132, Milan, Italy b Tumor Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, San Raffaele Scientific Institute, DIBIT, Via Olgettina 58, 20132, Milan, Italy

A R T I C L E I N F O

Article history: Received 15 May 2017 Accepted 6 June 2017 Available online xxx Keywords: Tumor microenvironment Immunosuppressive factors Dendritic cells T cells

A B S T R A C T

Tumor progression is accompanied by the production of a wide array of immunosuppressive factors by tumor and non-tumor cells forming the tumor microenvironment. These factors belonging to cytokines, growth factors, metabolites, glycan-binding proteins and glycoproteins are responsible for the establishment of immunosuppressive networks leading towards tumor promotion, invasion and metastasis. In pre-clinical tumor models, the inactivation of some of these suppressive networks reprograms the phenotypic and functional features of tumor-infiltrating immune cells, ultimately favoring effective anti-tumor immune responses. We will discuss factors and mechanisms identified in both mouse and human tumors, and the possibility to associate drugs inhibiting these mechanisms with new immunotherapy strategies already entered in the clinical practice. © 2017 Elsevier Ltd. All rights reserved.

1. Introduction The deep analysis of the tumor microenvironment has revealed in recent years several immunosuppressive networks dampening the anti-tumor immune responses both in mouse and human tumors. Some of these immunosuppressive networks are promoted by soluble factors produced and released by the tumor cells themselves or non-tumor cells within the tumor microenvironment [1]. Overall, the establishment of the immunosuppressive networks contributes to tumor growth, invasion and metastasis [2], both directly through the inhibition of immune cells crucially involved in the eradication of tumors, i.e. T cells and antigen presenting cells (APCs), and indirectly through the reprogramming of myeloid cells creating a hospitable and protective niche for

Abbreviations: APC, antigen presenting cells; CRD, carbohydrate recognition domain; DCs, dendritic cells; GDF-15, growth differentiation factor-15; IL, interleukin; IDO, indoleamine 2,3-dioxygenase; IFN-g, interferon-g; LXR, liver X receptors; M-CSF, macrophage-colony stimulating factor; mAbs, monoclonal antibodies; NO, nitric oxide; NOS, nitric oxide synthase; RNS, reactive nitrogen species; ROS, reactive oxygen species; SULT2B1b, sulfotransferase 2B1b; TCR, T cell receptor; TGF-b, transforming growth factor-b; TILs, tumor infiltrating lymphocytes; Th, T helper; TNF-a, tumor necrosis factor-a; TSLP, thymic stromal lymphopoietin; VEGF, vascular endothelial growth factor; XBP1, x-box-binding protein 1. * Corresponding authors. E-mail addresses: [email protected] (V. Russo), [email protected] (M.P. Protti).

metastasizing tumor cells [3]. Moreover, they also endow tumor cells with the ability to resist chemotherapy and immunotherapy [3] [4]. Soluble factors can dampen or shape distinct subsets of immune cells infiltrating the tumor microenvironment among which APCs, such as dendritic cells (DCs) and monocytes/macrophages, and T cells. Various immunosuppressive mechanisms have been identified so far, we will mainly discuss those induced by factors released by both mouse and human tumors with the ultimate goal to provide a rationale to combine drugs and immunotherapeutic drugs/strategies already on the market or close to enter the clinical arena in order to improve the anti-tumor immune response. 2. Tumor microenvironmental factors influencing DC function DCs play a key role in the induction of the antitumor immune response, as demonstrated by the ability of DC-based vaccines to induce objective clinical responses in cancer patients [5]. Recent reviews focusing on the mechanisms leading to DC dysfunction in solid tumors have been published [6,7], here we focus on the role of soluble factors present in the tumor microenvironment directly impacting on DC number and function. The factors/molecules that we will discuss are summarized in Table 1.

http://dx.doi.org/10.1016/j.cytogfr.2017.06.005 1359-6101/© 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: V. Russo, M.P. Protti, Tumor-derived factors affecting immune cells, Cytokine Growth Factor Rev (2017), http://dx.doi.org/10.1016/j.cytogfr.2017.06.005

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Table 1 Soluble factors affecting DC function. Molecule

Expressed by

Cytokines and growth Factors VEGF Tumor cells, IL-6 Tumor cells, M-CSF Tumor cells, IL-10 Tumor cells, TGF-b TSLP

Oncometabolites Lactic acid accumulation Triglycerides accumulation Oxysterols Adenosine accumulation

Function

Reference

endothelial cells immune cells immune cells immune cells

Inhibition of DC differentiation and maturation Inhibition of DC differentiation and maturation Inhibition of DC differentiation and maturation Inhibition of mono-DC differentiation and of antigen presenting capabilities of DCs. Increase of PDL1 expression Tumor cells, immune cells Down-regulation of DC costimulatory and presenting molecules. Inhibition of TNF-a and IL-12 production. Increase of PD-L1 expression Tumor cells, cancer associated Induction of naïve CD4+ T cells towards inflammatory Th2 cells fibroblasts

Tumor cells

[8] [11] [11] [19,20,7] [29,30,32,33] [36,37]

DC accumulation

Inhibition of mono-DC differentiation and of antigen presenting capabilities of DCs. Inhibition of IL- [47,46] 12 production. Reduction of DC antigen processing capabilities. XBP1 is involved in lipid-laden DC generation [48,50]

Tumors, immune cells Hypoxic tumor cells

Inhibition of CCR7-dependent DC migration. Induction of aberrant DC differentiation

2.1. Cytokines and growth factors In 1996 Gabrilovich and colleagues extensively investigated the role played by the Vascular Endothelial Growth Factor (VEGF) produced by human and mouse tumors on DCs [8]. They demonstrated that VEGF was able to impair the differentiation and maturation of DCs from hematopoietic precursors both in vitro and in vivo [8]. The inhibition of VEGF was reported to recover DC differentiation and maturation. Of note, studies investigating DC numbers in the blood of cancer patients inversely correlated with VEGF serum levels [9], thus suggesting the possibility that neutralizing VEGF by the well-known monoclonal antibody (mAb) bevacizumab could target at the same time both neoangiogenesis and DC recovery in cancer patients [10]. Interleukin (IL)-6 (IL-6) and the Macrophage-Colony Stimulating Factor (M-CSF), both produced by human renal carcinoma cells were reported to induce effects similar to those observed with VEGF. These factors were shown to inhibit the differentiation of CD14+CD1a precursors into DCs and to block the acquisition of APC function of the CD14 CD1a+-derived DCs [11]. Blocking these two cytokines with specific mAbs restored DC differentiation and APC function in vitro. Interestingly, it was also reported that IL-4 and IL-13 were able to reverse the inhibitory effects of tumorconditioned media or IL-6 plus M-CSF on the phenotypic and functional differentiation of CD34+ cells into DCs. In particular, IL-4 was found to act through the blockade of M-CSF and IL-6 receptortransducing chain (gp130) expression [12]. In ovarian cancer patients increased plasma levels of IL-8 and IL-6 correlated with the production of both cytokines by cultured ovarian cancer cell lines [13], and specific blockade of IL-6 and IL-8 production restored the T cell stimulatory activity of human DCs. IL-10 is the prototype of the anti-inflammatory cytokines and it is produced by innate and adaptive immune cells, including T cells, natural killer cells, as well as APCs [14] [15]. In cancer immunology IL-10 has been long considered an immunosuppressive cytokine: however, its role remains controversial (see also below) [16]. Several human and mouse tumors have been reported to release IL-10 [17]. In agreement with these data increased levels of IL-10 in the sera of patients affected by liver cancer were found to correlate with circulating DC subsets with an immature phenotype [18]. IL10 may affect DCs at distinct differentiation/maturation steps. The addition of IL-10 to human monocytes differentiating into DCs induced the development of macrophages with lower levels of

[61] [74]

MHC-II and the acquisition of markers typically expressed by macrophages, such as the nonspecific esterase and high levels of CD14, CD16 and CD68 [19,20]. When IL-10 was added to already differentiated DC, IL-10 induced only a slight reduction of MHC class II and CD1a expression, with no acquisition of the macrophage markers CD14, CD16 and CD68. Nevertheless, IL-10treated DCs, while acquiring high endocytic activity, were poor stimulators in mixed lymphocyte reaction and of tetanus toxinspecific T-cell lines [20]. Of note, a microarray analysis of monocyte-derived DCs treated with a combination of LPS and IL-10 showed a reduced expression of several LPS-inducible proinflammatory molecules and among genes uniquely modulated by the combined treatment PI3Kg was down-regulated while SOCS3 was up-regulated [21]. Tumor-derived IL-10 was also shown to inhibit CD40 expression, to suppress CD40-dependent IL-12 production, to decrease chemokine receptor expression, to blocks antigen presentation and to induce up-regulation of B7-H1/PD-L1 expression on DCs [7]. Accordingly, Steinbrink [22], and colleagues investigated the effect of IL-10-treated human DCs on the function of melanoma-associated antigen-specific CD8+ T cells and showed induction of antigen-specific anergy when tyrosinase-specific cytotoxic CD8+ T cells were co-cultured with IL-10-treated tyrosinase-pulsed DCs [22]. Interestingly, treatment of melanoma cells with the MEK inhibitor U0126 or RNA interference for BRAF V600E mutation was reported to decrease the production of IL-10, VEGF and IL-6 [23]. In addition, DCs treated with LPS and concomitantly exposed to supernatants of BRAF V600E silenced melanoma cells produced high levels of the inflammatory cytokines IL-12 and tumor necrosis factor-a (TNF-a), as compared to mock-treated melanoma cells. These effects were comparable to those observed with STAT3 silencing [23]. The above-reported immunosuppressive effects exerted by melanoma cells harboring the BRAF V600E mutation could be alleviated by the treatment with BRAF inhibitors. BRAF inhibitor-based treatments abrogated immunosuppression present in the tumor microenvironment of melanoma patients by increasing T-cell infiltration and function, improving NK cell activity as well as DC function [24]. These studies provide the rationale for the combination of target therapies and immune checkpoint blockers in melanoma patients. Indeed, both the blockade of the continuous BRAF V600E signaling and of the release of immunosuppressive cytokines, induced by selective BRAF inhibitors, would synergize with the invigoration of anti-tumor

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T-cells induced by anti-CTLA-4, anti-PD1 or anti-PD-L1 antibodies [25]. Transforming Growth Factor-b (TGF-b) has also been considered an immunosuppressive cytokine [26] and it has been shown to promote cancer by inducing loss of growth inhibitory control, enhancing tumor metastases and inhibiting the host immune response [27,28]. TGF-b is frequently present within the microenvironment of human and mouse tumors [7]. Tumor-derived TGF-b was shown to down-regulate the expression of the DC activation markers CD80, CD86, CD83 and MHC II molecules [29]. Moreover, it inhibited the expression of the pro-inflammatory cytokines TNF-a and IL-12, which are responsible for DC maturation [30], and affected DC motility and migration through a regulated expression of chemokines and chemokine receptors [30]. In addition to the inhibition of pro-inflammatory cytokines release, TGF-b was also shown to induce DCs to release immunosuppressive cytokines contributing to the generation of DCs endowed with tolerogenic capabilities that suppress the proliferation of effector anti-tumor T-cells and induce the conversion of T cells into T-regulatory cells [31,32]. Finally, TGF-b increased the expression of PD-L1 and STAT3 in DCs, further contributing to the development of immunosuppressive mechanisms based on T-cell effector blockade [33]. Other members of the TFG-b superfamily, such as the Growth Differentiation Factor-15 (GDF-15, macrophage inhibitory cytokine-1), were detected in tissues and serum samples of patients affected by glioblastoma, ovarian, prostate, gastric and colorectal cancers [34]. The addition of GDF-15 to differentiating human DCs inhibited the expression of CD83, CD86 and HLA-DR, downregulated IL-12 and up-regulated the production of TGF-b1. Overall, GDF-15-treated DCs retain functions associated to an immature state of differentiation, such as the phagocytic activity, while inhibiting the T-cell stimulatory activity. In agreement with these results, a vaccination approach based on the administration of GDF-15-treated DCs was significantly less effective in controlling tumor growth as compared to untreated DCs [34]. The thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine whose receptor is composed by a heterodimer of the IL-7 receptor a chain and a common g-like receptor chain called TSLP receptor (TSLPR). TSLP was shown to trigger DC-mediated allergic inflammation by conditioning DCs with T helper (Th)2polarizing capabilities (i.e., inducing naïve CD4+ T cells towards inflammatory Th2 cells secreting mostly IL-4, IL-5, IL-13 and TNFa) [35]. A role for TSLP released by tumor cells and cancer associated fibroblasts in breast cancer and pancreatic cancer, respectively, in Th2 development through conditioning of resident DCs has been reported [36,37]. Supernatants of breast cancer cells and pancreatic cancer associated fibroblasts were shown in vitro to drive myeloid DCs towards Th2 differentiation that was dependent on TSLP and TSLPR [37], and OX40L [36] signaling. Importantly, TSLPR expressing DCs were found in the tumor and in tumor draining but not in non-draining lymph nodes of pancreatic cancer patients [37] and OX40L expressing DCs accumulated in breast tumors [36]. More recently, basophils recruited into tumor draining lymph nodes of pancreatic cancer were shown to cooperate with TSLP-activated DCs by secretion of the IL-4 necessary for GATA-3 expression by Th2 cells [38]. 2.2. Oncometabolites and other molecules Areas of hypoxia and necrosis are common in tumors with limitation of nutrient availability for both tumor cells and immune cells. However, tumor cells develop a metabolic reprogramming, i.e., glycolysis even in the presence of oxygen (Warburg effect) [39], to sustain their own cell growth and proliferation depriving immune cells of nutrients essential for their function and survival or through the accumulation and secretion of metabolites, recently

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termed as oncometabolites, within the tumor microenvironment [40]. The conditioning of immune cell responses by metabolic challenging within the tumor microenvironment is increasingly becoming a matter of research as a mechanism of tumor immune escape. We refer to excellent published reviews [41–45], for extensive discussion: here we focus on the specific impact on DCs and T cells (see below). Lactic acid is frequently present within the tumor microenvironment as the end product of the Warburg effect (see also below) [39]. Lactic acid has been reported to inhibit IL-12 production and to dampen antigen presentation by DCs located in the tumor microenvironment [46]. Moreover, lactic acid impaired the differentiation of DCs from monocytes and blunted the inflammatory phenotype of DCs, inducing the production of IL-10 [47]. In recent years several reports have highlighted the immunosuppressive role exerted by lipids and cholesterol metabolites on DC function. In particular, DCs isolated from tumor-bearing mice and cancer patients were found to accumulate high levels of triglycerides as compared to healthy individuals [48]. Lipid accumulation was due to an increased uptake of extracellular lipids, which was mediated by the up-regulation of the scavenger receptor A. Lipid-laden DCs were poor stimulators of antigenspecific CD4+ T cells, an effect primarily due to low antigen processing capabilities of lipid-laden DCs, while the levels of costimulatory molecules expressed by DCs with high lipid content were similar to DCs with low lipid content isolated from the same tumor-bearing mice. Of note, the pharmacological normalization of the lipid content restored the functional activity of DCs and enhanced the therapeutic efficacy of cancer vaccines [48]. A clinical strategy based on the association of immune checkpoint blockers with drugs lowering lipid levels might be envisaged since lipid-laden DCs could be also isolated from cancer patients [49]. Different mechanisms can be responsible for the accumulation of lipids in DCs. Recently, the transcription factor X-box-binding protein 1 (XBP1), which is part of the endoplasmic reticulum stress response, has been tightly associated with the accumulation of intracellular lipids by tumor-infiltrating DCs [50]. Interestingly, such an accumulation failed to happen in tumor-infiltrating DCs isolated from XBP1-deficient mice. XBP1 deficiency also reduced the expression of genes involved in lipid biosynthetic pathways; thus, indicating XBP1 as a transcription factor involved in lipid accumulation in DCs undergoing cellular stress responses [50]. The stimuli present in the tumor microenvironment and responsible for the cellular stress responses are however still unknown. Since lipid-laden DCs induced an altered T-cell functionality [48], it is not surprising that XBP1 deletion restored the surface expression of MHC-I/peptide complexes in DCs, as well as the anti-tumor CD4+ and CD8+ T cells in the microenvironment of tumor-bearing mice [48]. These results indicate that targeting XBP1 may have a relevant therapeutic value. Therefore, strategies interfering with or inactivating XBP1 might be used, in combination with immunotherapy, to enhance antigen presentation by DCs and effective generation of anti-tumor T cells. Cholesterol metabolites have recently been reported to establish immune suppressive networks associated to the tumor growth. In particular, oxidized products of cholesterol, i.e. oxysterols, generated by reactive oxygen species (ROS) have been reported to blunt the inflammation by inhibiting the expression of a specific set of pro-inflammatory genes, such as COX-2, MMP9, IL6, CCL2, TNF-a, nitric oxide synthase (NOS) and IL-1b in macrophages and DCs [51]. The attenuation of inflammation mediated by oxysterols is strictly dependent on the nuclear Liver X Receptors a (LXRa) (also known as NR1H3) and LXRb (NR1H2) [52], as evaluated both in vitro and in vivo. Since LXRs and oxysterols were primarily reported to be involved in cholesterol homeostasis, these results provided initial evidence of an

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integrated pathway between inflammation and lipid metabolism and identified the LXR/LXR ligand axis as a highly regulated program modulating the inflammatory responses [53]. Oxysterols may be also generated through specific enzymatic reactions involving several cholesterol hydroxylases [54,55]. How these enzymes are regulated is largely unknown, with the exception of specific pathophysiologic processes, as discussed below [56]. The mechanisms through which oxysterols released in the microenvironment would exert immunoregulatory functions are still debated. Of note, oxidized membranes from dying cells activate LXRs once phagocytosed by macrophages and/or DCs. This pathway has been described to occur in non-transformed cells undergoing apoptosis [57]. Macrophages associated to breast tumors developing in the PyMT-MMTV model produced the 27-HC oxysterol through the activity of the Cyp27a1 cholesterol hydroxylase [58]. This observation further emphasizes the multiple pathways responsible for oxysterol generation within the tumor microenvironment. It has been shown that tumor-derived oxysterols shape the number and function of immune cells infiltrating the tumor microenvironment [59]. We recently reported that pancreatic neuroendocrine tumor cells over-express the cholesterol hydroxylase Cyp46a1, which generates the oxysterol 24S-HC during tumor progression [56]. The over-expression of Cyp46a1 occurs during the transition of the hyperplastic pancreatic neuroendocrine islets into angiogenic islets, a process governed by a neutrophil-dependent angiogenic switch [56]. In agreement with these results, we showed that 24S-HC attracted pro-angiogenic neutrophils within the tumor microenvironment by exploiting the G-protein coupled receptor CXCR2 [56,60], a process occurring independently of LXR signaling [60]. The blockade of the oxysterol/ CXCR2 axis induced a marked decrease of intratumor neutrophils that was accompanied with a strong delay of the tumor growth [60]. Oxysterols have also been shown to inhibit the expression of the chemokine receptor CCR7 on maturing DCs, thereby dampening their migration to draining lymph nodes and consequent induction of successful anti-tumor immune responses [61]. In several human tumor histotypes, such as breast, lung, gastric, colon and pancreatic carcinomas, we reported the presence of CD83+CCR7 DCs infiltrating the tumors [61]. Differently from the migration of neutrophils, the inhibition of CCR7 required the engagement of LXRa isoform, as demonstrated by short hairpin RNA experiments specifically deleting the LXRa receptor [61]. The failure of tumor-infiltrating DCs to migrate towards lymphoid organs was associated to the lack of a robust anti-tumor immune response in distinct pre-clinical tumor models [61]. Distinct strategies can be pursued to inactivate oxysterols. A simple way to decrease their intratumor concentration deals with the use of blood cholesterol-lowering drugs, such as statins [62]. Statins block the cholesterol biosynthetic pathway by inhibiting the hydroxymethylglutaryl-CoA reductase, a rate-limiting enzyme along the pathway of cholesterol synthesis [63]. However, the blockade of this pathway also affects the formation of isoprenoids that are extremely important in the formation of prenylated proteins, such as Rho, Rac, CDC42, which are involved in cell motility, including DCs and T cells [62]. The use of drugs inhibiting the cholesterol biosynthetic pathway downstream mevalonate can overcome this limitation. Zaragozic acid, a squalene synthase inhibitor [64], blocking the intratumor generation of oxysterols [65] but leaving intact the formation of isoprenoids, delayed tumor growth in immuno-competent mice without interfering with isoprenoid formation. Targeting specific cholesterol hydroxylases should be considered as an alternative strategy in individuals with normal blood levels of cholesterol. Oxysterols can also be enzymatically inactivated by sulfotransferases [66,67]. In

particular, the enzyme sulfotransferase 2B1b (SULT2B1b) catalyzes the sulfation of certain cholesterol hydroxyl groups [66,67]. Tumors constitutively expressing SULT2B1b were delayed or rejected only when injected in immunocompetent mice [68]. Accordingly, SULT2B1b-tumors were infiltrated by DCs expressing high levels of CCR7 [61]. Overall, the anti-tumor effects mediated by the inactivation of LXR/LXR ligand axis provide the rationale to test combination therapies based on immune checkpoint blockers together with drugs (i.e. statins or zaragozic acid) or strategies (SULT2B1b) counteracting the LXR/LXR ligand axis. Adenosine may accumulate in the tumor microenvironment through different mechanisms. Hypoxic tumor cells release adenosine by hydrolyzing ATP [69], and concentrations of adenosine were increased in tumors compared to normal tissue [70]. In addition, adenosine can be produced in the tumor microenvironment by ectonucleotidases CD39 and CD73 expressed at the surface of tumor cells and normal leucocytes [71–73]. Adenosine exerts several immunomodulatory effects via adenosine receptors expressed on different immune cells, including DCs. DCs differentiated in the presence of adenosine induce tumor growth when injected in tumor-bearing mice, possibly due to the expression of a wide array of angiogenic, proinflammatory and immunosuppressive molecules, including VEGF, TGF-b, IL-6, IL-8, IL-10, COX-2 and indoleamine 2,3-dioxygenase (IDO) [74]. 3. Tumor microenvironmental factors influencing T cell function Tumor infiltrating lymphocytes (TILs) comprise a variable size of the total immune cells present within the tumor microenvironment that depends on the tumor type and they have been shown to variably impact on tumor prognosis and response to therapy [75,76]. Several parameters, which define the tumor immune contexture, such as the type of T cells, their location and density within the tumor and their functional orientation, have been identified to dictate the final contribution of TILs to tumor rejection or tumor promotion [75]. Immune checkpoint inhibitors (e.g., anti-CTLA4, anti-PD-1 and anti-PDL-1), which have been specifically designed to amplify spontaneous anti-tumor T cell responses, have revolutionized cancer treatment [77]. However, although immune checkpoint inhibitors have reached notable success in melanoma and nonsmall-cell lung carcinoma [77], translation of their use to other tumors has proven more difficult. Resistance mechanisms to immune checkpoint blockade in cancer comprise both tumorintrinsic and -extrinsic factors, among which multiple immunosuppressive mechanisms operating in the tumor microenvironment that ultimately interfere with T cell function [78]. These mechanisms vary in different tumors and their extent possibly correlate with the variable success of immune checkpoint blockade in different tumors. Several recent reviews focusing on the mechanisms leading to T cell dysfunction in solid tumors have been published [2,44,79–84], here we focus on the role of soluble factors present in the tumor microenvironment directly impacting on T cell activation and effector function. The factors/molecules that we will discuss are summarized in Table 2. 3.1. Cytokines, growth factors and chemokines As reported above, several cytokines and chemokines are present within the tumor that can be produced by tumor cells themselves or by stromal and immune cells in the tumor microenvironment. As cytokines have multiple pleiotropic effects on several cell types with reciprocal influence, the direct effect on T

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Table 2 Soluble factors in the tumor microenvironment affecting T cell recruitment and function. Molecule

Expressed by

Function

Reference

Cytokines and chemokines IL-10

Tumor cells, immune cells

Inhibits T cell proliferation, at high concentration induces proliferation of intratumor CD8+ T cells Inhibits T cell secretion of cytolytic cytokines Prevents CD8+ T cell infiltration in the tumor

[85–87]

Prevent T cell infiltration

[93]

TGF-b CXCL12 Nitrated CCL2

Metabolic dysfunctions Glucose restriction IDO-induced reduction of tryptophan and increase of kynurenine Arginase-and NOS-induced arginine depletion Glutamine restriction Lactic acid accumulation Reactive nitrogen species (RNS) Adenosine accumulation

Other molecules Galectin-1

Galectin-3

Galectin-9 Tenascin-C

Tumor cells, immune cells Tumor cells, cancer associated fibroblasts Myeloid derived suppressor cells through production of RNS

Increased uptake by tumor cells

Reduce T cell activation and proliferation, alter cytokine production and TCR signaling Overexpressed in tumors and Tryptophan deprivation prevents T cell proliferation. upregulated in many cells in response Kynurenine interferes with TCR signaling by down-modulation of CD3 expression to IFN-g or can induce T cell death Reduced expression of the CD3j chain in T cells, effector function, survival and Overexpressed in tumors differentiation of memory T cells Increased uptake by tumor cells Reduced proliferation and cytokine secretion Tumor cells Suppress T cell activation and proliferation, prevents TCR-triggered phosphorylation of JNK, c-Jun, p38 and NFAT activation Myeloid derived suppressor cells Impair T cell signaling, activation, proliferation and migration

[91] [92]

[94–97] [100,101]

[105,106] [103] [107–111] [112,113]

Hypoxic tumor cells

Inhibits T cell activation and expansion, suppresses cytotoxic activity of T and NK [116–119] cells and in vitro cytokine production and lytic activity by T cells

Tumor cells, monocytes, activated B and T cells, mesenchymal stromal cells Tumor cells, monocytes, activated B and T cells, mesenchymal stromal cells Tumor cells, monocytes, activated B and T cells Tumor cells

Impairment in TCR signaling, apoptosis of activated T cell, elimination of Th1 and [127– Th17 cells 130] Impairment in TCR cross-linking, dysfunction in synapse formation and TCR [131– downregulation, CTLA-4 trapping (prolongation of inhibitory signals), interaction 139] with LAG-3 (dampening of antitumor immunity) [137,140] Induction of apoptosis, binding to TIM-3 (T-cell exhaustion) Inhibition of T cell migration and proper activation

cell function has been demonstrated so far only for a limited number of molecules. A direct effect of IL-10 on T cell was demonstrated by Taga and collaborators [85], who showed that treatment of CD3-triggered T cells with IL-10 in the absence of monocytes induces direct inhibition of T cell growth and IL-2 production. On the other hand, IL-10 could induce activation and proliferation of intratumoral CD8+ T cells, particularly at higher concentration [86,87], suggesting that the opposing effects of IL-10 observed on T cell function might be concentration dependent. A positive role for IL-10 in tumor rejection was also demonstrated in preclinical tumor models where pegylated recombinant murine IL-10 induced rejection of large tumors and metastases that was mediated by CD8+ T cells [88]. Recently, based on these data, a phase I study with pegylated IL-10 in patients with advanced, treatmentrefractory solid tumors reported an acceptable toxicity profile and evidence of anti-tumor activity, especially in renal cell cancer [89]. Collectively, the overall contribution of IL-10 to the immunosuppressive microenvironment deserves more experimental evidence. The immunosuppressive role of TGF-b on T cell effector function was demonstrated by challenging with TGF-b producing tumors mice whose T cells had been rendered resistant to TGF-b expression. These mice were able to mount an immune response, eliminate the tumor burden and survive [90]. The molecular mechanisms of T cell dysfunction induced by TGF-b in vivo were later elucidated. TGF-b was shown to act on cytotoxic T

[142,143]

lymphocytes to inhibit the expression of cytolytic gene products, namely perforin, granzyme A and B, Fas ligand and interferon (IFN)-g [91]. Repression of granzyme B and IFN-g involved binding of TGF-b-activated Smad and ATF1 transcription factors to their promoter regions, indicating direct and selective regulation by the TGF-b/Smad pathway [91]. Strategies specifically targeting TGF-b signaling pathway in T cells should prove efficacious in reprogramming T cell functions and may help in tumor rejection. Chemokines are relevant factors promoting T cell recruitment to the tumor, thus dysfunction in T cell attracting chemokines may impact on intratumoral T cell infiltration. In a mouse model that recapitulates the features of human pancreatic cancer, CXCL12 secretion by cancer associated fibroblasts prevented CD8+ T cell infiltration and lysis of tumor cells [92]. Importantly, treatment with a CXCL12 antagonist induced T cell accumulation among cancer cells that acted synergistically with anti-PD-L1 therapy to promote cancer regression [92]. Impairment in chemokine function has been reported by Molon and collaborators [93], who showed that, in preclinical murine models, CCL2 nitration due to reactive nitrogen species (RNS) in the tumor microenvironment (see below), hindered T cell infiltration. This resulted in the trapping of tumor-specific T cells in the stroma surrounding cancer cells. Of note, preconditioning of the tumor microenvironment with drugs able to inhibit CCL2 modification facilitated cytotoxic T cell invasion of the tumor [93]. Modulation of soluble factors that affect T cell infiltration to the

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tumor is particularly relevant in case of cancer immunotherapies based on adoptive transfer of tumor reactive T cells. 3.2. Metabolic dysfunctions Glucose constitutes a predominant nutrient for rapidly diving cells and tumor cells commonly outcompete immune cells for glucose uptake. Insufficient levels of glucose were shown to reduce T cell activation and proliferation [94,95], and to alter T cell cytokine secretion [95–97]. Importantly, therapeutic approaches aimed at restoring glucose content in the tumor microenvironment by therapeutic treatment with anti-PD-L1, which decreased activation of the Akt-mTOR pathway and reduced tumor cell glycolysis [98], or by inducing aerobic glycolysis by genetically engineering T cells [95], improved anti-tumor activity. Deprivation of amino acids essential for T cells has also been recognized as an immune escape mechanism. Tryptophan deprivation is the consequence of upregulation of IDO, which catalyzes the first step in tryptophan catabolism along the kynurenine pathway. IDO is overexpressed in a variety of tumors and is upregulated in many cells in response to IFN-g [99]. Tryptophan depletion and consequent metabolic byproducts directly suppressed anti-tumor T cells by preventing T cell proliferation [100] and the kinurenine byproducts could interfere with T cell receptor (TCR) signaling by downregulating CD3 expression or induced T cell death [101,102]. Glutamine deprivation has been also reported as a limiting factor for T cells, which use increased amounts of glutamine as a metabolic substrate during activation and exhibit reduced proliferative capacity and cytokine secretion when glutamine concentrations are low [103]. L-arginine is another amino acid that plays a critical role in anti-tumor T cell immunity and it is often depleted in tumors [104]. The enzymes NOS and arginase are critical for L-arginine metabolism and many tumors overexpress one or both of these enzymes [104]. Arginine deficiency affected protein synthesis in activated T cells, provoking a reduction in the expression of the CD3j chain [105]. In addition, the presence of arginine during T cell activation promoted effector function, survival and memory T cell differentiation, and T cells with increased L-arginine levels displayed enhanced anti-tumor activity in a murine model [106]. As mentioned above, the metabolism of tumor cells can generate high amount of lactic acid due to upregulation of glycolytic enzymes and hypoxia at the tumor site. While tumor cells can respond to extracellular acidosis and maintain redox balance by altering expression of pH-regulating proteins, excess extracellular lactate in T and NK cells results in disruption of aerobic glycolysis with decreased production of IFN-g [107–111]. Within the tumor microenvironment the oxidation of arginine by NOS produces nitric oxide (NO), which can interact with ROS to generate RNS. RNSs negatively affected T cell meditated immunity by interfering with T cell signaling, activation, proliferation and migration [112,113]. On the other hand, NO production by intratumor DCs could promote tumor destruction by adoptively transferred CD8+ T cells [114], indicating that NO can have dual protumor and anti-tumor activity [115]. Accumulation of adenosine was shown to inhibit T cell activation and expansion [116], to suppress T cell function and NK cell cytotoxicity [117,118], and in vitro cytokine production and lytic activity of CD8+ and CD4+ T cells [119]. 3.3. Other molecules Galectins belong to a family of endogenous glycan-binding proteins that can influence immune cell functions [120–122]. They are classified in three groups based on their structure but the ones

mostly involved in cancer immunosuppression are galectin-1, which belongs to the “proto-type” group containing a carbohydrate recognition domain (CRD) that can dimerize; galectin-9, which belongs to the “tandem-repeat” group that contains two CRD in tandem, and chimera-type galectin-3, which displays a CRD connected to a non-lectin N-terminal region responsible for oligomerization [121]. Galectins are externalized through a still unknown unconventional route [121], and can be released by tumor cells and monocyte-derived cells but also activated B and T cells [123–125] . It is becoming increasingly clear that galectins play key roles in shaping T cell biology and therefore tumor immunity by influencing T cell activation, signaling and survival [126]. Galectin-1 was shown to antagonize TCR signaling [127], and to trigger T cell apoptosis [128,129]. Interestingly, galectin-1 selectively eliminated Th1 and Th17 cells expressing the glycans for galectin-1 binding but not Th2 cells that were protected from death via a2,6 sialylation of surface glycoprotein [130]. Galectin-3 was also shown to interfere with TCR function by preventing TCR, CD4 and Lck clustering [131,132], and to induce anergy of TILs by limiting the formation of a functional synapse by preventing optimal LFA-1 triggering with reduced adhesion to target cells [133,134], and promoting TCR down-modulation [135]. In addition, galectin-3 directly killed activated T cells [136]. Galectin-9 was shown to induce apoptosis through the calcium-calpain-caspase-1 pathway [137]. Finally, galectins can play direct inhibitory roles by binding relevant glycosylated receptors at the T cell surface. Indeed, galectin-3-N-glycan complexes could trap CTLA-4 and prolong the inhibitory signals triggered by this immune checkpoint receptor [138]. In addition, galectin-3 was shown to dampen anti-tumor responses through interactions with LAG-3 on the surface of CD8+ T cells [139] and galectin-9 to bind TIM-3 leading to T-cell exhaustion [140]. Tenascin-C is an extracellular matrix disulfide-linked hexameric glycoprotein that is highly expressed in the microenvironment of solid tumors [141]. Tenascin-C has been shown to affect malignant transformation, uncontrolled tumor cell proliferation, angiogenesis, metastasis and escape from immunesurveillance [141]. In tumor immunology an inhibitory effect of tenascin-C on T cell migration was reported in glioma [142]. More recently, in a mouse model of prostatic cancer, cancer stem cells used tenascin-C to inhibit TCR-dependent activation, proliferation and cytokine production through interaction with a5b1 integrin on the surface of T cells [143]. 4. Concluding remarks Soluble factors released by tumor cells and non-tumor cells within the tumor microenvironment are endowed with a vast array of immunosuppressive effects. These effects dampen both the innate and the adaptive components of tumor-infiltrating immune cells, such as DCs and T cells. Tumor-derived immunosuppressive factors belong to cytokines, growth factors, glycoproteins and glycan-binding proteins and metabolites, particularly oncometabolites, generated by dysregulated metabolic pathways frequently associated to the requirements and metabolic adaptations of tumor cells. Of note, some molecules/factors might be neutralized or blocked by clinical-grade reagents, such as antibodies, antagonists and inhibitors. In the near future, it is conceivable to test at pre-clinical and clinical levels the combination of immune checkpoint blockers and clinical-grade reagents counteracting the above-reported soluble factors in order to augment effective anti-tumor immune responses.

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Authorship V.R. and M.P.P. researched and wrote this article. Conflict of interest statement The authors declare no conflicts of interest. Acknowledgment This work was supported by grants from the Italian Association for Cancer Research (AIRC)(IG-19016 to Vincenzo Russo and IG19119 to Maria Pia Protti).

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