Myeloid-derived suppressor cell impact on endogenous and adoptively transferred T cells

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ScienceDirect Myeloid-derived suppressor cell impact on endogenous and adoptively transferred T cells Ainhoa Arina1 and Vincenzo Bronte2 Novel models of autochthonous tumorigenesis and adoptive T cell therapy (ATT) are providing new clues regarding the pro-tumorigenic and immunosuppressive effects of myeloidderived suppressor cells (MDSC), and their interaction with T cells. New findings are shifting the perception of the main level at which MDSC act, from direct cell-to-cell suppression to others, such as limiting T cell infiltration. Adoptively transferred, high-avidity T cells recognizing peptides with high-affinity for MHC-I eliminated large tumors. However, low-avidity T cells or low-affinity peptides resulted in failure to eradicate tumors. Manipulation of intratumoral myeloid cells improved the outcome of otherwise unsuccessful ATT. Therefore, therapeutic intervention directed at the tumor stroma might be required when using suboptimal T cells for ATT. Addresses 1 Department of Radiation and Cellular Oncology, The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA 2 Verona University Hospital, Department of Pathology and Diagnostics, 37134 Verona, Italy Corresponding authors: Arina, Ainhoa ([email protected]) and Bronte, Vincenzo ([email protected])

Current Opinion in Immunology 2015, 33:120–125 This review comes from a themed issue on Tumour immunology Edited by Philip D Greenberg and Hans Schreiber

http://dx.doi.org/10.1016/j.coi.2015.02.006 0952-7915/# 2015 Published by Elsevier Ltd.

Introduction

Oncogene-induced autochthonous cancers [1,2,3,4] have confirmed the critical role of cancer-secreted GM-CSF in driving accrual and function of CD11b+Gr1+ myeloid-derived suppressor cells (MDSC) [5,6], which counteract T cell responses against tumors [7], as already shown in transplantable models [5,6]. Findings from other transgenic tumor models suggest that oncogene-driven tumors can be immunogenic, and generate T cell responses that delay tumor onset [1,8,9], although a few transformed cells escaping immune control are enough to allow cancer progression [9]. Introduction of strong antigens was required for epigenetic selection of low-immunogenicity/antigen-loss variants in Kras/p53 oncogene-driven sarcomas [1], suggesting that these tumors Current Opinion in Immunology 2015, 33:120–125

are less immunogenic than tumors induced by UV light and 3-methylcholanthrene, where immune selection occurred without exogenous introduction of model antigens [10–12], or viral SV40 oncogene-driven tumors [9], where SV40 oncogene/antigen was retained and caused local T cell tolerization. These different mechanisms to evade the immune response may represent different clinical scenarios (e.g., viral vs. non-viral oncogene activation, or mutagen-induced cancer). Indeed cancer patients show different degrees of activation of spontaneous T cell responses [13]. Some tumors, for example, melanomas, present a high number of potentially immunogenic mutations [14]. Additional evidence is needed to understand whether patients with weaker spontaneous responses correspond to those with tumors presenting fewer mutations, or those endowed with more potent cancer-related immune suppression. Since ATT will become a major therapeutic modality, it is important to determine whether MDSC in the tumor microenvironment can suppress cancer eradication by the adoptively transferred T cells. Previous studies using live microscopy of surgically exposed tumors in the EL4/EG7 thymoma model showed cancer antigen-dependent T cell arrest [15] and specific killing of antigen (Ag)+ cells that were interspersed among Ag cancer cells [16]. The time required for killing a single cancer cell was estimated to be 6 h, but the observed bystander killing of Ag cancer cells was minimal [16]. Since most tumors contain at least some Ag cancer cells, achieving some level of bystander killing of these malignant cells that cause relapse is essential for tumor eradication. In the surgically exposed tumors analyzed in the earlier studies, the animal needed to be sacrificed after the imaging session; therefore, the subsequent changes in the imaged tumor could not be followed up. A recent study using a window chamber-based imaging technique [17] allowed, for the first time, real-time longitudinal analysis of the same tumor before, during and after ATT until full eradication or relapse. In this system, significant bystander killing of Ag cells occurred, consistent with earlier experiments [18]. Massive vessel destruction was observed using transgenic T cells targeting a model antigen [17], or natural tumor-specific T cells targeting autochthonous tumor-specific antigens [19]. In contrast to IFNg and TNF [20], perforin was not required for the eradication of the large solid tumors established for several weeks [17]. Stable, cognate antigen-dependent interactions of T cells with stromal cells resulted in the production of higher amounts of IFNg compared to interactions with www.sciencedirect.com

MDSC impact on endogenous and transferred T cells Arina and Bronte 121

cancer cells [17]. This higher relevance of IFNg than perforin in vivo is consistent with previous studies [21,22] and it might underlie the reported 6 h-requirement for cancer cell apoptosis. More studies are required to determine whether the effects on vessels are mediated by IFNg, either directly or indirectly, through the induction of fas/fasL [22,23], or other mechanisms. We will therefore review the most recent advances in understanding the impact of cells of myeloid lineage, and in particular of MDSC, on anti-tumor T cells.

Impact of MDSC on endogenous T cell responses Initial studies reported the ability of cells recognized by the anti-CD11b (Mac-1) and anti-Gr1 monoclonal antibodies and induced by growing tumors [5,24–30] to suppress T cell priming in vivo [5,7,28–30] and effector function in vitro [5,7,27,29,30]. The in vitro assays to test inhibition of T cell function (most frequently proliferation or IFN-g release) by MDSC, were adopted as surrogate for MDSC’s ability to suppress T cell responses. Recently, however, it has become clear that in vitro suppression does not always correlate with in vivo inhibition of T cell responses. For example, tumors growing in immunodeficient hosts induced systemic MDSC and tumorinfiltrating macrophages that were strongly suppressive in vitro; however, those same cells were not able to prevent tumor eradication by adoptively transferred tumor-specific T cells [19]. Similarly, MDSC showed the ability to suppress CTL function in vitro without reflecting the immune status of mice, which could be as diverse as tumor-induced tolerance, neonatal tolerance to tumor antigens, or even systemic immunity against the tumor [4]. Experimental evidence to explain the differences between in vivo and in vitro suppression by MDSC principally indicates three factors: cytokines secreted by tumors, the immune-independent, tumor-promoting effects of MDSC, and a different sensitivity of naı¨ve vs. effector T cells to suppression by MDSC. Whereas other cytokines might expand MDSC from precursors, GM-CSF can license them for full immunosuppressive function [4,5,6,27]. This role is further strengthened by evidence from pancreatic autochthonous tumor models, in which GMCSF produced by the Kras oncogene-transformed cancer cells mediated development and recruitment of MDSC, necessary for tumor progression from pre-invasive stage. The presence of MDSC in tumor was required to counteract prevention of tumor growth by tumor-specific T cells [2,3]. It remains unclear at what level the unique suppressive effect of GMCSF-induced MDSC takes place, but pancreatic model studies suggest an effect in restraining tumor infiltration by T cells. Alternatively, the tumor-promoting functions of MDSC, which are distinct and independent from T cell suppression, www.sciencedirect.com

are well documented and might be more important than immunoregulatory activity for many cancers. Indeed, MDSC promote tumor growth in the absence of an adaptive immune system [24–26] and can facilitate angiogenesis [31] and metastasis [32,33]. Finally, activation status of T cells seems to play an important role in sensitivity to suppression by MDSC. Most studies showing suppression of T cell responses use naı¨ve T cells as responders. An explanation for increased sensitivity of naı¨ve T cells to suppression by MDSC might relate to MDSC’s ability to down-regulate L-selectin levels on T cells; this resulted in decreased homing to lymph nodes where T cells would be activated [34]. Indeed, the function of primed, tumor-specific T cells isolated from lymph nodes was suppressed by MDSC in vitro but not in vivo [29]. In vitro studies suggest that tumor cells, but not MDSC, can directly suppress the effector, lytic machinery of T cells isolated from tumors [35]. Consistent with these findings, adoptively transferred tumor-specific memory T cells but not naı¨ve T cells eliminated tumors established in immunodeficient mice that had systemic and intratumoral MDSC but not Tregs [19]. In addition, pre-existing endogenous T cell memory responses were not affected by systemic immune suppression in tumor-bearing mice harboring MDSC as well as Tregs [19].

Impact of MDSC on ATT Three possible outcomes have been described for tumorinfiltrating myeloid cells after ATT, in tumors that responded to therapy: 1. Elimination: an increase in non-viable stromal cells was observed in tumors treated with T cells recognizing CD11b+ cells that cross-present antigen from neighboring cancer cells [18,36,37]. 2. Change: in many cases, the anti-tumoral effects of ATT required a change in either subset distribution or phenotype of MDSC, typically toward a more proinflammatory and less suppressive phenotype [38,39]. Such change can be pursued experimentally with the aim of altering MDSC differentiation and hence increase efficacy of ATT. In fact, the ability of lowdose chemotherapy to function as adjuvant for poorly effective CD8T cells recognizing mouse telomerase antigen was related to long-term elimination of proliferating, Ly6Chi suppressive cells in the marginal zone of the spleen of tumor-bearing hosts [40,41]. 3. No elimination or detectable phenotypic changes: Under certain conditions, ATT can achieve tumor eradication without detectable changes in the composition or phenotype of intratumoral myeloid cells [19]. Differences in the tumor microenvironment or in the ‘quality’ of T cells could explain these varying scenarios. Current Opinion in Immunology 2015, 33:120–125

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Tumor microenvironment can determine the level of immune suppression: key factors GM-CSF

GM-CSF controls acquisition of the most suppressive phenotype by MDSC. Consistently, MDSC induced by GM-CSF-overexpressing B16 tumors impaired the antitumor effect of adoptively transferred, melanoma-specific pmel T cells, by limiting T cell infiltration [42]. CSF-1/M-CSF

CSF-1/M-CSF is a critical regulator of the Ly6C+ monocytes and their differentiation into tumor-associated macrophages [43]. Several female reproductive cancers secrete CSF-1 [44,45]. A small molecule inhibitor of CSF-1, PLX3397, reduced the number of tumor-associated macrophages and polarized the remaining, leading to increased infiltration by adoptively transferred T cells and enhanced antitumor effects [46]. Concurring with these results, treatment with anti-CSF-1-receptor mAb caused reduction in tumor-infiltrating macrophages in mouse and human tumors, and clinical objective responses in diffusetype giant cell tumors [47]. G-CSF

G-CSF is critical for the production of neutrophils that, by producing elastase and TIMP-free MMP9, play a pivotal role in the activation of latent TGF-b and in freeing stromal progenitors from their reservoirs [48]. Molecular programs in tumor-infiltrating myeloid cells

Control of cEBPb transcription factor by microRNA 1423p and the stress-response protein CHOP is key to drive the immunosuppressive program in MDSC within the tumor environment, in part by modulating their response to locally produced IL-6 [49–51]. Interfering with this molecular pathway enhances the therapeutic activity of otherwise ineffective antitumor CD8+ T cells [49]. HMGB1

HMGB1, produced by intratumoral macrophages, downregulates L-selectin on T cells while attracting MDSC progenitors [52]. Effects of the microbiota

In a recent study, gut microbiota ‘primed’ myeloid cells to produce TNF and ROS that mediated antitumor effects of CpG immunotherapy and platinum chemotherapy, respectively, in the absence of adaptive immunity [53]. However, whether microbiota dysbiosis can negatively influence ATT requires further investigation. Immunosuppressive effects of non-myeloid tumor stroma

Stromal cells expressing FAP (Fibroblast Activation Protein) suppress T cell responses against tumors [54]. Recent studies indicate the dense extracellular matrix and fibroblast-derived CXCL12 as key factors ‘sequestering’ T cells away from tumor cells [55,56,57]. Current Opinion in Immunology 2015, 33:120–125

Tumor burden

Immune suppression and/or T cell dysfunction induced by tumors impair T cell-mediated tumor destruction [58,59]. In a murine lymphoma model, high tumor burdens induced tumor-Ag-specific T cell dysfunction, which was not mediated by MDSC, but by cancer cells presenting antigen [60]. A low non-lymphoablative dose of chemotherapy before the ATT led to an antitumoral effect, through reduction of tumor burden below a critical threshold.

The quality of T cells can determine the outcome of ATT Not all T cells are equal

As discussed, antigen-experienced effector or memory T cells seem to be more intrinsically resistant to suppression by MDSC than naı¨ve T cells. Retrospective analysis of clinical trials using adoptively transferred TILs for melanoma patients show that the parameters correlating with tumor regression include the absolute numbers of infused T cells, short in vitro culture duration, CD27 expression in vivo on transferred CD8+ T cells, and cells with a higher capacity to proliferate and persist following ATT [61]. Preclinical studies suggest that T cell donor age can critically determine an optimal T cell quality for ATT as well [62]. A high functional avidity of TCR is also desirable. Avidity is closely related to affinity, although the contribution of affinity to avidity seems to reach a plateau around 10 mM [63]. Interestingly, six TCRs found in human melanomas, with affinities ranging between 1.4 and 60 mM, produced similar antitumoral effects in vivo. A TCR with affinity of 99 nM, however, conferred poorer antitumoral activity. Since the affinity range of natural TCR is about 1–100 nM, these results suggest that TCRs with affinities in the lower side of the natural range should be avoided for ATT. However, TCRs with high avidity for self-antigens might expose the T cell bearing them to a more robust tolerization [64]. Not all targets are equal

After multiple clinical trials using T cells that targeted antigens expressed by the tumor and normal tissues, it is increasingly clear that the efficacy of such shared Ags will always be limited by sometimes life-threatening autoimmunity, because antitumoral effect and autoimmunity go ‘hand in hand’ [65]. Consistently, in human melanoma, the TCR affinity threshold for antitumor effects and autoimmunity is the same [63]. Therefore, the choice of target antigens should be ideally directed to unique tumor-specific antigens, generated by either somatic mutations or viral infection. As an acceptable alternative, antigens shared by tumors and non-essential tissues can also be used (such as CD19). Another important aspect of target selection is the affinity for MHC-I. Contrary to TCR affinity, which has a relatively minor contribution to the outcome of ATT, the affinity of the target peptide for presenting MHC class I molecules can predict either www.sciencedirect.com

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Figure 1

Chemotherapy Radiotherapy MDSC blockade

Cancer cells High-affinity Ag

Low-affinity Ag

IFN-γ

High-avidity T cell

Low-avidity T cell

Ag crosspressentation

Myeloid cell

No other therapy required

Combination therapy required Current Opinion in Immunology

Two distinct scenarios following ATT. Left panel: high-avidity interactions between TCR and MHC-I/tumor-antigen peptide complexes on stromal cells are sufficient to allow tumor eradication by release of cytokines, such as IFN-g, affecting vascular and stromal compartment including MDSC. Right panel: below a certain avidity threshold, ATT is ineffective unless combined with other treatments capable to alter the immunosuppressive microenvironment. These include, chemotherapy and radiotherapy, which can affect both cancer and stromal cells, or more selective treatments specifically targeting MDSC, here representing the myeloid component with immune regulatory function within the tumor. In this diagram, only myeloid cells are shown for simplicity, but other stromal cell components might also contribute to the outcome of ATT, as detailed in the article.

tumor eradication or relapse [66]. High affinities (less than 10 nM) were required for tumor eradication, which is a narrow window considering that the affinity range measured for natural peptides was between 1 and 20 000 nM. Consistently, TILs from patients who had objective responses to ATT recognized high-affinity mutant tumor-specific peptides [67,68]. Recent advances in wholeexome sequencing and class I MHC binding-prediction now enable the identification of tumor-specific neoantigens for individual patients [69]. Therefore, choosing tumor-specific neoantigens with the highest MHC class I molecule affinity will be critical for optimal ATT results.

Conclusions Three elements determine the success of ATT: tumor microenvironment, quality of T cells and quality of the antigen targeted. Based on available evidence, we propose that proficient, ‘high-quality T cells’ targeting tumor-specific peptides with high affinity to the presenting MHC molecule could be sufficient therapy for cancer. ‘Suboptimal T cells’ could require additional therapeutic intervention directed at modifying the tumor microenvironment, to help T cells overcome immune suppression posed by myeloid cells, cancer cells and fibroblastic stroma (Figure 1).

Acknowledgments This work was supported by grants from the Italian Ministry of Health; Italian Ministry of Education (FIRB cup: B31J11000420001), Universities,

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and Research; Italian Association for Cancer Research (AIRC, grants 6599, 12182 and 14103) to V.B, as well as the Ludwig Foundation (A.A.). We especially thank Leticia Corrales for artwork design and Amy Huser for editorial help.

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Current Opinion in Immunology 2015, 33:120–125