A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells

Singer, Meromit; Wang, Chao; Cong, Le; Marjanovic, Nemanja D.; Kowalczyk, Monika S.; Zhang, Huiyuan; Nyman, Jackson; Sakuishi, Kaori; Kurtuluş, Sema; Gennert, David; Xia, Junrong; Kwon, John; Nevin, James; Herbst, Rebecca H.; Yanai, Itai; Rozenblatt-Rosen, Orit; Kuchroo, Vijay K.; Regev, Aviv; Anderson, Ana C.

doi:10.1016/j.cell.2017.11.006

Cited by 88 publications

(102 citation statements)

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“…Compared to PD‐1 int and 4‐1BB neg PD‐1 high CD8 + TILs, we found that 4‐1BB pos PD‐1 high CD8 + TILs showed the highest levels of T‐cell activation markers and TCR‐responsive transcription factors as well as significant enrichment for T‐cell‐activation–related gene signatures. Importantly, a T‐cell activation gene signature that is uncoupled from dysfunction was specifically enriched in the 4‐1BB pos PD‐1 high subpopulation, but not in the 4‐1BB neg PD‐1 high and PD‐1 int subpopulations. 4‐1BB pos PD‐1 high CD8 + TILs also displayed the highest proportion of the tumor‐reactive CD39 + CD103 + subset, indicating that the prominent T‐cell activation likely resulted from increased tumor reactivity of 4‐1BB pos cells.…”

Section: Discussionmentioning

confidence: 96%

4‐1BB Delineates Distinct Activation Status of Exhausted Tumor‐Infiltrating CD8+ T Cells in Hepatocellular Carcinoma

et al. 2019

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Background and Aims Targeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly 4‐1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor‐infiltrating CD8+ T cells (CD8+ tumor‐infiltrating lymphocytes [TILs]) and its association with distinct T‐cell activation features among exhausted CD8+ TILs in hepatocellular carcinoma (HCC). Approach and Results Tumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA‐sequencing, and in vitro functional restoration assays. Among the examined costimulatory receptors, 4‐1BB was most prominently expressed on CD8+ TILs. 4‐1BB expression was almost exclusively detected on CD8+ T cells in the tumor—especially on programmed death 1 (PD‐1)high cells and not PD‐1int and PD‐1neg cells. Compared to PD‐1int and 4‐1BBnegPD‐1high CD8+ TILs, 4‐1BBposPD‐1high CD8+ TILs exhibited higher levels of tumor reactivity and T‐cell activation markers and significant enrichment for T‐cell activation gene signatures. Per‐patient analysis revealed positive correlations between percentages of 4‐1BBpos cells among CD8+ TILs and levels of parameters of tumor reactivity and T‐cell activation. Among highly exhausted PD‐1high CD8+ TILs, 4‐1BBpos cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4‐1BB–related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4‐1BB agonistic antibodies enhanced the function of CD8+ TILs and further enhanced the anti‐PD‐1–mediated reinvigoration of CD8+ TILs, especially in cases showing high levels of T‐cell activation. Conclusion 4‐1BB expression on CD8+ TILs represents a distinct activation state among highly exhausted CD8+ T cells in HCC. 4‐1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T‐cell activation.

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Section: Discussionmentioning

confidence: 96%

4‐1BB Delineates Distinct Activation Status of Exhausted Tumor‐Infiltrating CD8+ T Cells in Hepatocellular Carcinoma

et al. 2019

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“…Comparing the transcriptome of TILs from wild‐type (WT) mice (activated and exhausted) and MT1 −/− mice (activated and not exhausted) highlighted a cluster of genes overexpressed in the WT group that had not previously been reported in transcriptional profiles of activation, and which was validated in a single‐cell RNAseq dataset from human melanoma. The top‐ranking gene in this signature was the transcription factor GATA‐3, a crucial factor in Th2 differentiation, and also recently reported to promote induced Treg function …”

Section: T‐cell Exhaustionmentioning

confidence: 85%

“…Tim‐3 and PD‐1 co‐expression has been reported in different animal models of cancer, as well as in human disease including our findings in glioblastoma. Moreover, PD‐1 and Tim‐3 single or double expression defines a hierarchy of dysfunction of TILs in melanoma models, where the most profound impairment in cytokine production and proliferation was reported for PD‐1 + Tim‐3 + T cells . Blocking both Tim‐3 and PD‐1 has also revealed a more effective strategy than blocking PD‐1 alone in preclinical models.…”

Section: Checkpoint Receptor Immunotherapymentioning

confidence: 99%

Co‐inhibitory blockade while preserving tolerance: checkpoint inhibitors for glioblastoma

Lucca

Hafler

2017

Immunological Reviews

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Summary The introduction of immunotherapy with checkpoint receptor blockade has changed the treatment of advanced cancers, at times inducing prolonged remission. Nevertheless, the success rate of the approach is variable across patients and different tumor types, and treatment is often accompanied by severe immune-related side effects, suggesting the importance of co-inhibitory pathway for both prevention of autoimmunity and failure of tumor rejection. A better understanding of how to uncouple anti-tumor activity from loss of self-tolerance is necessary in order to increase the therapeutic efficacy of checkpoint immunotherapy. In this review, we describe basic concepts of T cell exhaustion that occur in cancer, highlighting the role of co-inhibitory receptors in contributing to this process while preventing immunopathology. By providing an overview of the current therapeutic success and immune-related burden of secondary effects of checkpoint immunotherapy, we illustrate the “double-edged sword” related to interference with immune-regulatory pathways. Finally, since achieving tumor rejection while preserving self-tolerance is particularly important for the central nervous system, we analyze the case for checkpoint immunotherapy in glioblastoma, the most common adult brain tumor.

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“…Single‐cell transcriptomic technologies have enabled the exciting discovery of novel cell populations within various in vivo contexts (Paul et al , ; Satija et al , ; Baron et al , ; Shekhar et al , ; Singer et al , ; Villani et al , ; Jia et al , ; Kernfeld et al , ; Vento‐Tormo et al , ; Chapuy et al , ; Kurtulus et al , ; Spallanzani et al , ). Following the discovery of a new cell population of interest based on full transcriptome analysis (of typically a few thousand genes), follow‐up studies require succinct gene marker panels by which the cells of interest can be distinguished from the general cell population (Fig ).…”

Section: Introductionmentioning

confidence: 99%

Combinatorial prediction of marker panels from single‐cell transcriptomic data

Delaney

Schnell

Cammarata

et al. 2019

Molecular Systems Biology

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Single‐cell transcriptomic studies are identifying novel cell populations with exciting functional roles in various in vivo contexts, but identification of succinct gene marker panels for such populations remains a challenge. In this work, we introduce COMET, a computational framework for the identification of candidate marker panels consisting of one or more genes for cell populations of interest identified with single‐cell RNA‐seq data. We show that COMET outperforms other methods for the identification of single‐gene panels and enables, for the first time, prediction of multi‐gene marker panels ranked by relevance. Staining by flow cytometry assay confirmed the accuracy of COMET's predictions in identifying marker panels for cellular subtypes, at both the single‐ and multi‐gene levels, validating COMET's applicability and accuracy in predicting favorable marker panels from transcriptomic input. COMET is a general non‐parametric statistical framework and can be used as‐is on various high‐throughput datasets in addition to single‐cell RNA‐sequencing data. COMET is available for use via a web interface (http://www.cometsc.com/) or a stand‐alone software package (https://github.com/MSingerLab/COMETSC).

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A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells

Cited by 88 publications

References 0 publications

4‐1BB Delineates Distinct Activation Status of Exhausted Tumor‐Infiltrating CD8+ T Cells in Hepatocellular Carcinoma

4‐1BB Delineates Distinct Activation Status of Exhausted Tumor‐Infiltrating CD8+ T Cells in Hepatocellular Carcinoma

Co‐inhibitory blockade while preserving tolerance: checkpoint inhibitors for glioblastoma

Combinatorial prediction of marker panels from single‐cell transcriptomic data

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