SLAMF6 as a Regulator of Exhausted CD8+ T Cells in Cancer

Yigit, Burcu; Wang, Ninghai; Hacken, Elisa ten; Chen, Shih‐Shih; Bhan, Atul K.; Suárez‐Fueyo, Abel; Katsuyama, Eri; Tsokos, George C.; Chiorazzi, Nicholas; Wu, Catherine J.; Burger, Jan A.; Herzog, Roland W.; Engel, Pablo; Terhorst, Cox

doi:10.1158/2326-6066.cir-18-0664

Cited by 46 publications

(36 citation statements)

References 55 publications

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“…Our RNA-seq and ATAC-seq data revealed that Tox −/− P14 cells had a reduced expression of Slamf6 which was accompanied by massive changes in chromatin accessibility. Interestingly, SLAMF6 is an inhibitory receptor which is highly co-expressed with TCF-1 in the progenitor-like subset of exhausted CD8+ T cells in cancer 42 . We thus compared the expression of SLAMF6 and PD-1 in TCF-1 hi and TCF-1 lo subsets, respectively, in Tox +/+ and Tox −/− P14 cells.…”

Section: Resultsmentioning

confidence: 99%

Persistence of self-reactive CD8+ T cells in the CNS requires TOX-dependent chromatin remodeling

et al. 2021

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Self-reactive CD8+ T cells are important mediators of progressive tissue damage in autoimmune diseases, but the molecular program underlying these cells’ functional adaptation is unclear. Here we characterize the transcriptional and epigenetic landscape of self-reactive CD8+ T cells in a mouse model of protracted central nervous system (CNS) autoimmunity and compare it to populations of CNS-resident memory CD8+ T cells emerging from acute viral infection. We find that autoimmune CD8+ T cells persisting at sites of self-antigen exhibit characteristic transcriptional regulation together with distinct epigenetic remodeling. This self-reactive CD8+ T cell fate depends on the transcriptional regulation by the DNA-binding HMG-box protein TOX which remodels more than 400 genomic regions including loci such as Tcf7, which is central to stemness of CD8+ T cells. Continuous exposure to CNS self-antigen sustains TOX levels in self-reactive CD8+ T cells, whereas genetic ablation of TOX in CD8+ T cells results in shortened persistence of self-reactive CD8+ T cells in the inflamed CNS. Our study establishes and characterizes the genetic differentiation program enabling chronic T cell-driven immunopathology in CNS autoimmunity.

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Section: Resultsmentioning

confidence: 99%

Persistence of self-reactive CD8+ T cells in the CNS requires TOX-dependent chromatin remodeling

et al. 2021

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“…Intracellular staining of Tc cells showed that effector markers, lysosomal CD107a and granzyme B, and IL-2 expressing Tc cells were significantly increased in number. A lower percentage of CD8+PD-1+ TILs in anti-SLAMF6 injected mice were found compared to the control group, which suggests the activation of Tc’s in the tumor [ 130 ]. There is also a relation between the SLAMF6 gene and PDAC.…”

Section: Inhibitory Receptorsmentioning

confidence: 99%

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Saka

Gökalp

Piyade

et al. 2020

Cancers

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T-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to neutralize inhibitory receptors by a single agent or combinatorial immune checkpoint inhibitors to boost effector function, PDAC remains unresponsive to these therapies, suggesting that multiple molecular mechanisms play a role in stimulating the exhaustion state of tumor-infiltrating T cells. Recent studies utilizing transcriptomics, mass cytometry, and epigenomics revealed a critical role of Thymocyte selection-associated high mobility group box protein (TOX) genes and TOX-associated pathways, driving T-cell exhaustion in chronic infection and cancer. Here, we will review recently defined molecular, genetic, and cellular factors that drive T-cell exhaustion in PDAC. We will also discuss the effects of available immune checkpoint inhibitors and the latest clinical trials targeting various molecular factors mediating T-cell exhaustion in PDAC.

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“…The so called exhCD8 T cells progenitor population can be defined as PD-1 int (36) CXCR5 + (51) or Slamf6 + /Ly108 (38,52) lacking expression of TIM-3 ( 51), while terminally exhCD8 T cells are identified as PD-1 hi (36,37) or TIM-3 + (37, 51). Although several transcription factors have been proposed as key determinants of exhaustion programs, recent studies highlighted a dynamic interplay between T Cell Factor-1 (TCF-1) and thymocyte selection-associated high mobility group box protein (TOX), in the control of different exhausted populations (51,(53)(54)(55)(56).…”

Section: Cd8 T Cell Exhaustionmentioning

confidence: 99%

Hypoxia Supports Differentiation of Terminally Exhausted CD8 T Cells

et al. 2021

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Hypoxia, angiogenesis, and immunosuppression have been proposed to be interrelated events that fuel tumor progression and impair the clinical effectiveness of anti-tumor therapies. Here we present new mechanistic data highlighting the role of hypoxia in fine-tuning CD8 T cell exhaustion in vitro, in an attempt to reconcile seemingly opposite evidence regarding the impact of hypoxia on functional features of exhausted CD8 T cells. Focusing on the recently characterized terminally-differentiated and progenitor exhausted CD8 T cells, we found that both hypoxia and its regulated mediator, vascular endothelial growth factor (VEGF)-A, promote the differentiation of PD-1+ TIM-3+ CXCR5+ terminally exhausted-like CD8 T cells at the expense of PD-1+ TIM-3- progenitor-like subsets without affecting tumor necrosis factor (TNF)-α and interferon (IFN)-γ production or granzyme B (GZMB) expression by these subpopulations. Interestingly, hypoxia accentuated the proangiogenic secretory profile in exhausted CD8 T cells. VEGF-A was the main factor differentially secreted by exhausted CD8 T cells under hypoxic conditions. In this sense, we found that VEGF-A contributes to generation of terminally exhausted CD8 T cells during in vitro differentiation. Altogether, our findings highlight the reciprocal regulation between hypoxia, angiogenesis, and immunosuppression, providing a rational basis to optimize synergistic combinations of antiangiogenic and immunotherapeutic strategies, with the overarching goal of improving the efficacy of these treatments.

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SLAMF6 as a Regulator of Exhausted CD8+ T Cells in Cancer

Cited by 46 publications

References 55 publications

Persistence of self-reactive CD8+ T cells in the CNS requires TOX-dependent chromatin remodeling

Persistence of self-reactive CD8+ T cells in the CNS requires TOX-dependent chromatin remodeling

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Hypoxia Supports Differentiation of Terminally Exhausted CD8 T Cells

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