Clonal replacement of tumor-specific T cells following PD-1 blockade

Yost, KE; Satpathy, AT; Wells, DK; Qi, Y; Wang, C; Kageyama, R; McNamara, KL; Granja, JM; Sarin, KY; Brown, RA; Rk, Gupta; Curtis, C; Bucktrout, SL; Mm, Davis; Chang, ALS; Chang, HY

doi:10.21417/ky2019nm

Cited by 218 publications

(351 citation statements)

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“…With above‐mentioned approach, one can address this question with tumor‐infiltrating immune cells collected before and on treatment. Applying scRNA‐seq analysis to characterize intratumoral immune cell changes to anti‐PD‐1 have started to emerge 126 . Alternatively, T cells in a given cancer type but with different outcomes to checkpoint blockades can be compared at single cell level.…”

Section: Discussionmentioning

confidence: 99%

“…CD39, which had been initially identified as a specific T exh cell marker during chronic infection 80 was found to mark T exh cells in several cancers. CD39 has since become a relevant cancer immunotherapeutic candidate 16,81,82 . Finally, beyond transcript‐level markers of exhaustion, it has been argued that an epigenetic signature may be the most robust marker of exhaustion 83,84 .…”

Section: Tumor‐infiltrating T Cell Clusters Identified By Scrna‐seqmentioning

confidence: 99%

“…However, a separate study showed that responsiveness to checkpoint blockade was predicated on a low ratio of T exh cells within melanoma lesions 81 . Another recent study tracked site‐matched melanoma lesions before and after checkpoint blockade to better understand the origins and phenotypes of tumor‐reactive CD8 + clonotypes 82 . Surprisingly, while checkpoint blockade preferentially expanded T exh ‐like cells, those clones were mostly not matched in pretreatment infiltrates.…”

Section: Tumor‐infiltrating T Cell Clusters Identified By Scrna‐seqmentioning

confidence: 99%

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Unravelling the heterogeneity and dynamic relationships of tumor-infiltrating T cells by single-cell RNA sequencing analysis

Chaudhry

Rapaport

et al. 2020

Journal of Leukocyte Biology

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T cells are crucial for the success of immune‐based cancer therapy. Reinvigorating antitumor T cell activity by blocking checkpoint inhibitory receptors has provided clinical benefits for many cancer patients. However, the efficacy of these treatments varies in cancer patients and the mechanisms underlying these diverse responses remain elusive. The density and status of tumor‐infiltrating T cells have been shown to positively correlate with patient response to checkpoint blockades. Therefore, further understanding of the heterogeneity, clonal expansion, migration, and effector functions of tumor‐infiltrating T cells will provide fundamental insights into antitumor immune responses. To this end, recent advances in single‐cell RNA sequencing technology have enabled profound and extensive characterization of intratumoral immune cells and have improved our understanding of their dynamic relationships. Here, we summarize recent progress in single‐cell RNA sequencing technology and current strategies to uncover heterogeneous tumor‐infiltrating T cell subsets. In particular, we discuss how the coupling of deep transcriptome information with T cell receptor (TCR)‐based lineage tracing has furthered our understanding of intratumoral T cell populations. We also discuss the functional implications of various T cell subsets in tumors and highlight the identification of novel T cell markers with therapeutic or prognostic potential.

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Section: Discussionmentioning

confidence: 99%

Section: Tumor‐infiltrating T Cell Clusters Identified By Scrna‐seqmentioning

confidence: 99%

Section: Tumor‐infiltrating T Cell Clusters Identified By Scrna‐seqmentioning

confidence: 99%

See 1 more Smart Citation

Unravelling the heterogeneity and dynamic relationships of tumor-infiltrating T cells by single-cell RNA sequencing analysis

Chaudhry

Rapaport

et al. 2020

Journal of Leukocyte Biology

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“…Moreover, blocking PD‐1 after sufficient priming or concurrent with vaccination can enhance tumor immunity. This is supported by elegant work by Chang and colleagues, elucidating the mechanism by which PD‐1 blockade enhances T cell immunity . By coupling T cell receptor (TCR) and transcriptional sequencing, they tracked T cell clones at a single‐cell resolution prior to and after anti‐PD‐1 therapy, conclusively demonstrating that the therapeutic impact of PD‐1 blockade was not derived from reinvigorating exhausted TILs, but rather restricting the exhaustion of new distinct novel clonotypes that are nascently primed.…”

Section: The Promise Of Vista In Cancer Immunotherapymentioning

confidence: 95%

VISTA: Coming of age as a multi-lineage immune checkpoint

ElTanbouly

Schaafsma

Noelle

et al. 2020

Clinical and Experimental Immunology

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The immune response is governed by a highly complex set of interactions among cells and mediators. T cells may be rendered dysfunctional by the presence of high levels of antigen in the absence of co-stimulation while myeloid cells may be programmed towards an immunosuppressive state that promotes cancer growth and metastasis while deterring tumor immunity. In addition, inhibitory programs driven by immune checkpoint regulators dampen anti-tumor immunity. The ideal cancer immunotherapy treatment will improve both cross-priming in the tumor microenvironment and relieve suppression by the inhibitory checkpoints. Recently, blockade of programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) has elicited impressive results, but not in all patients, so additional targets are under investigation. V-set immunoglobulin domain suppressor of T cell activation (VISTA) is a novel immunoregulatory receptor that is broadly expressed on cells of the myeloid and lymphoid lineages, and is frequently implicated as a poor prognostic indicator in multiple cancers. Importantly, antibody targeting of VISTA uniquely engages both innate and adaptive immunity. This, combined with the expression of VISTA and its non-redundant activities compared to other immune checkpoint regulators, qualifies VISTA to be a promising target for improving cancer immunotherapy.

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“…However, anti‐PD‐1 therapy in transplantable mouse tumor models such as MC38 colon cancer does not depend upon lymph node priming [59,60]. Nevertheless, recent single‐cell RNA and T cell receptor sequencing data from basal or squamous cell carcinoma tumors showed that the expansion of T cell clones did not derive from pre‐existing tumor‐infiltrating T lymphocytes [61]. Novel clones may, therefore, derive from tumor‐extrinsic sources including lymph nodes.…”

Section: How Does Inflammasome Activation Reinforce Tumor Immunity Trmentioning

confidence: 99%

Role of inflammasome activation in tumor immunity triggered by immune checkpoint blockers

Segovia

Russo

Girotti

et al. 2020

Clinical and Experimental Immunology

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Immune checkpoint blockers improve the overall survival of a limited number of patients among different cancers. Identifying pathways that influence the immunological and clinical response to treatment is critical to improve the therapeutic efficacy and predict clinical responses. Recently, a key role has been assigned to innate immune mechanisms in checkpoint blockade-driven anti-tumor responses. However, inflammatory pathways can both improve and impair anti-tumor immunity. In this review, we discuss how different inflammatory pathways, particularly inflammasome activation, can influence the clinical outcome of immune checkpoint blockers. Inflammasome activation may reinforce anti-tumor immunity by boosting CD8 + T cell priming as well as by enhancing T helper type 17 (Th17) responses. In particular, we focus on the modulation of the cation channel transmembrane protein 176B (TMEM176B) and the ectonucleotidase CD39 as potential targets to unleash inflammasome activation leading to reinforced anti-tumor immunity and improved efficacy of immune checkpoint blockers. Future studies should be aimed at investigating the mechanisms and cell subsets involved in inflammasome-driven anti-tumor responses.

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Clonal replacement of tumor-specific T cells following PD-1 blockade

Cited by 218 publications

References 0 publications

Unravelling the heterogeneity and dynamic relationships of tumor-infiltrating T cells by single-cell RNA sequencing analysis

Unravelling the heterogeneity and dynamic relationships of tumor-infiltrating T cells by single-cell RNA sequencing analysis

VISTA: Coming of age as a multi-lineage immune checkpoint

Role of inflammasome activation in tumor immunity triggered by immune checkpoint blockers

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