Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance

Palmer, Douglas C.; Guittard, Geoffrey; Franco, Zulmarie; Crompton, Joseph G.; Eil, Robert L.; Patel, Shashank J.; Ji, Yun; Panhuys, Nicholas J. Van; Klebanoff, Christopher A.; Sukumar, Madhusudhanan; Clever, David; Chichura, Anna; Roychoudhuri, Rahul; Varma, Rajat; Wang, Ena; Gattinoni, Luca; Marincola, Francesco M.; Balagopalan, Lakshmi; Samelson, Lawrence E.; Restifo, Nicholas P.

doi:10.1084/jem.20150304

Cited by 163 publications

(144 citation statements)

References 88 publications

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“…In contrast, besides Havcr2 (encoding Tim3) and Prdm1 (encoding Blimp1), Tim3 high Blimp1 high CD8 T cells had higher expression of other genes associated with T cell exhaustion, including Cd244, Il10 , and Cish (Fig. 1C and table S1) (30). Evaluation of protein confirmed that TCF1 high CD8 T cells expressed lower levels of surface 2B4 and LAG3, despite having slightly higher surface PD1, on day 7 after infection (Fig.…”

Section: Resultsmentioning

confidence: 99%

The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness

et al. 2016

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During chronic viral infections and in cancer, T cells become dysfunctional, a state known as T cell exhaustion. Although it is well recognized that memory CD8 T cells account for the persistence of CD8 T cell immunity after acute infection, how exhausted T cells persist remains less clear. Using chronic infection with lymphocytic choriomeningitis virus clone 13 and tumor samples, we demonstrate that CD8 T cells differentiate into a less exhausted TCF1high and a more exhausted TCF1low population. Virus-specific TCF1high CD8 T cells, which resemble T follicular helper (TFH) cells, persist and recall better than do TCF1low cells and act as progenitor cells to replenish TCF1low cells. We show that TCF1 is both necessary and sufficient to support this progenitor-like CD8 subset, whereas cell-intrinsic type I interferon signaling suppresses their differentiation. Accordingly, cell-intrinsic TCF1 deficiency led to a loss of these progenitor CD8 T cells, sharp contraction of virus-specific T cells, and uncontrolled viremia. Mechanistically, TCF1 repressed several pro-exhaustion factors and induced Bcl6 in CD8 T cells, which promoted the progenitor fate. We propose that the TCF1-Bcl6 axis counteracts type I interferon to repress T cell exhaustion and maintain T cell stemness, which is critical for persistent antiviral CD8 T cell responses in chronic infection. These findings provide insight into the requirements for persistence of T cell immune responses in the face of exhaustion and suggest mechanisms by which effective T cell–mediated immunity may be enhanced during chronic infections and cancer.

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Section: Resultsmentioning

confidence: 99%

The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness

et al. 2016

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“…Alternatively, modulation of TCR signaling thresholds to enhance T cell activation and function has also been explored [12, 92, 93]. Because several miRNAs have been found to influence TCR signaling by targeting key inhibitory phosphatases [47], they may be promising candidates to manipulate for this purpose.…”

Section: Harnessing Mirna Biology To Enhance Adoptive T Cell Immunothmentioning

confidence: 99%

“…Advances in our understanding of the biological mechanisms behind the effectiveness of adoptive T cell therapy have underscored the importance of the qualities of transferred T cells [3] and revealed the complexity of the inhibitory barriers posed by the host and tumor cells that need to be overcome for the success of the treatment [4, 5]. Among T cell factors, the avidity of the T cell receptor (TCR) or chimeric antigen receptor (CAR) [6, 7], the proliferative and survival capacities [8–11], and the ability to sustain effector functions within the tumor [12] have been shown to be crucial determinants for triggering the eradication of malignant cells.…”

Section: Introductionmentioning

confidence: 99%

Enhancing adoptive T cell immunotherapy with microRNA therapeutics

Hocker

Gattinoni

2016

Seminars in Immunology

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Adoptive T cell-based immunotherapies can mediate complete and durable regressions in patients with advanced cancer, but current response rates remain inadequate. Maneuvers to improve the fitness and antitumor efficacy of transferred T cells have been under extensive exploration in the field. Small non-coding microRNAs have emerged as critical modulators of immune system homeostasis and T cell immunity. Here, we summarize recent advances in our understanding of the role of microRNAs in regulating T cell activation, differentiation, and function. We also discuss how microRNA therapeutics could be employed to fine-tune T cell receptor signaling and enhance T cell persistence and effector functions, paving the way for the next generation of adoptive immunotherapies.

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“…5B). Cish is a SOCS and SH2 domain protein, diminishes JAK/STAT signaling (46), and affects tumor-infiltrating CD8 + TCR responsiveness (47). Regulator of G-protein signaling (RGS) molecules control immune cell migration and activation.…”

Section: Resultsmentioning

confidence: 99%

Molecular Programming of Tumor-Infiltrating CD8+ T Cells and IL15 Resistance

Doedens

Rubinstein

Gross

et al. 2016

Cancer Immunology Research

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Despite clinical potential and recent advances, durable immunotherapeutic ablation of solid tumors is not routinely achieved. IL15 expands NK, NKT, and CD8+ T-cell numbers and engages the cytotoxic program, and thus is under evaluation for potentiation of cancer immunotherapy. We found that short-term therapy with IL15 bound to soluble IL15 receptor α–Fc (IL15cx; a form of IL15 with increased half-life and activity) was ineffective in the treatment of autochthonous PyMT murine mammary tumors, despite abundant CD8+ T-cell infiltration. Probing of this poor responsiveness revealed that IL15cx only weakly activated intratumoral CD8+ T cells, even though cells in the lung and spleen were activated and dramatically expanded. Tumor-infiltrating CD8+ T cells exhibited cell-extrinsic and cell-intrinsic resistance to IL15. Our data showed that in the case of persistent viral or tumor antigen, single-agent systemic IL15cx treatment primarily expanded antigen-irrelevant or extratumoral CD8+ T cells. We identified exhaustion, tissue-resident memory, and tumor-specific molecules expressed in tumor-infiltrating CD8+ T cells, which may allow therapeutic targeting or programming of specific subsets to evade loss of function and cytokine resistance, and in turn, increase the efficacy of IL2/15 adjuvant cytokine therapy.

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Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance

Abstract: Palmer et al. find that Cish, a member of the SOCS family, is induced by TCR stimulation in CD8+ T cells and inhibits their functional avidity against tumor. The authors uncover a novel mechanism of suppression for a SOCS member.

Cited by 163 publications

References 88 publications

The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness

The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness

Enhancing adoptive T cell immunotherapy with microRNA therapeutics

Molecular Programming of Tumor-Infiltrating CD8+ T Cells and IL15 Resistance

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