Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers

Scheper, Wouter; Kelderman, Sander; Fanchi, Lorenzo F.; Linnemann, Carsten; Bendle, Gavin; Rooij, Marije A. J. de; Hirt, Christian; Mezzadra, Riccardo; Slagter, Maarten; Dijkstra, Krijn K.; Kluin, Roelof J.C.; Snæbjörnsson, Pétur; Milne, Katy; Nelson, Brad H.; Zijlmans, Henry; Kenter, Gemma G.; Voest, Emile E.; Haanen, John B.A.G.; Schumacher, Ton N.

doi:10.1038/s41591-018-0266-5

Cited by 454 publications

(390 citation statements)

References 33 publications

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“…These cells co-expressed several markers of T cell dysfunction, as well as markers previously shown to enrich for tumorspecific T cells, including CD39 and CD103 13,[37][38][39] . These results suggest that tumor recognition, clonal expansion, and T cell dysfunction are intimately linked processes, and that the TME contains a large number of 'bystander' T cells, as has been previously suggested 13,52 . Second, tracking individual T cell clones before and after therapy in sitematched specimens provided insights into the origin of clonally-expanded T cells.…”

Section: Discussionsupporting

confidence: 77%

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

Yost

Satpathy

Wells

et al. 2019

Preprint

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Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of cancer patients. However, which tumor-specific T cells are mobilized following checkpoint blockade remains unclear. Here, we performed paired single-cell RNA-and T cell receptor (TCR)-sequencing on 79,046 cells from site-matched tumors from patients with basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) preand post-anti-PD-1 therapy. Tracking TCR clones and transcriptional phenotypes revealed a coupling of tumor-recognition, clonal expansion, and T cell dysfunction: the T cell response to treatment was accompanied by clonal expansions of CD8 + CD39 + T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, this expansion did not derive from pre-existing tumor infiltrating T cell clones; rather, it comprised novel clonotypes, which were not previously observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8 + T cells, compared to other distinct T cell phenotypes, and was evident in BCC and SCC patients. These results, enabled by single-cell multi-omic profiling of clinical samples, demonstrate that pre-existing tumor-specific T cells may be limited in their capacity for re-invigoration, and that the T cell response to checkpoint blockade relies on the expansion of a distinct repertoire of T cell clones that may have just recently entered the tumor.

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Section: Discussionsupporting

confidence: 77%

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

Yost

Satpathy

Wells

et al. 2019

Preprint

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“…A likely explanation is that the EM-like compartment is enriched in non tumor-specific cells, as multiple studies have shown the presence of large numbers of "bystander" T cells in human tumors (Simoni et al, 2018;Scheper et al, 2019) Figure 6 D), which is essential to establish and maintain the epigenetic T cell exhaustion program enabling T cells to persist in the context of chronic antigenic stimulation (Alfei et al, 2019;Khan et al, 2019;Scott et al, 2019;Yao et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Deciphering the transcriptomic landscape of tumor-infiltrating CD8 lymphocytes in B16 melanoma tumors with single-cell RNA-Seq

Carmona

Siddiqui

Bilous

et al. 2019

Preprint

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Recent studies have proposed that tumor-specific tumor-infiltrating CD8 + T lymphocytes (CD8 TIL) can be classified into two main groups: "exhausted" TILs, characterized by high expression of the inhibitory receptors PD-1 and TIM-3 and lack of transcription factor 1 (Tcf1); and "memory-like" TILs, with self-renewal capacity and co-expressing Tcf1 and PD-1. However, a comprehensive definition of the heterogeneity existing within both tumor-specific and total CD8 TILs has yet to be clearly established.To investigate this heterogeneity at the transcriptomic level, we performed paired single-cell RNA and TCR sequencing of CD8 T cells infiltrating B16 murine melanoma tumors, including cells of known tumor specificity. Unsupervised clustering and gene signature analysis revealed four distinct CD8 TIL states -exhausted, memory-like, naïve and effector memory-like (EM-like) -and predicted novel markers, including Ly6C for the EM-like cells, that were validated by flow cytometry. Tumor-specific PMEL T cells were predominantly found within the exhausted and memory-like states but also within the EM-like state. Further, TCR repertoire sequencing revealed a large clonal expansion of exhausted, memory-like and EM-like cells with partial clonal relatedness between them. Finally, meta-analyses of public bulk and single-cell RNAseq data suggested that anti-PD-1 treatment induces expansion of EM-like cells.Our reference map of the transcriptomic landscape of murine CD8 TILs will help interpreting future bulk and single-cell transcriptomic studies and may guide the analysis of CD8 TIL subpopulations in response to therapeutic interventions.2

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“…Cancers that harbor a low mutational burden can also be associated with this form of 1° resistance. Leukemias, pediatric malignancies, and many epithelial cancers often possess a modest number of somatic mutations and a corresponding limited neoantigen load, restricting the number of potential TCR targets . Overcoming primary T cell‐intrinsic resistance is centered on expanding the TCR repertoire.…”

Section: Therapeutic Resistance To Tcr‐based Cancer Immunotherapiesmentioning

confidence: 99%

“…Leukemias, pediatric malignancies, and many epithelial cancers often possess a modest number of somatic mutations and a corresponding limited neoantigen load, 185 restricting the number of potential TCR targets. 224 Overcoming primary T cell-intrinsic resistance is centered on expanding the TCR repertoire. This can be accomplished by the ex vivo introduction of a TCR conferring antitumor specificity into non-specific T cells through genetic engineering followed by ACT.…”

Section: Primary T Cell-intrinsic Resistancementioning

confidence: 99%

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Chandran

Klebanoff

2019

Immunological Reviews

224

185

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Adoptive cell transfer (ACT) using chimeric antigen receptor (CAR)‐modified T cells can induce durable remissions in patients with refractory B‐lymphoid cancers. By contrast, results applying CAR‐modified T cells to solid malignancies have been comparatively modest. Alternative strategies to redirect T cell specificity and cytolytic function are therefore necessary if ACT is to serve a greater role in human cancer treatments. T cell receptors (TCRs) are antigen recognition structures physiologically expressed by all T cells that have complementary, and in some cases superior, properties to CARs. Unlike CARs, TCRs confer recognition to epitopes derived from proteins residing within any subcellular compartment, including the membrane, cytoplasm and nucleus. This enables TCRs to detect a broad universe of targets, such as neoantigens, cancer germline antigens, and viral oncoproteins. Moreover, because TCRs have evolved to efficiently detect and amplify antigenic signals, these receptors respond to epitope densities many fold smaller than required for CAR‐signaling. Herein, we summarize recent clinical data demonstrating that TCR‐based immunotherapies can mediate regression of solid malignancies, including immune‐checkpoint inhibitor refractory cancers. These trials simultaneously highlight emerging mechanisms of TCR resistance. We conclude by discussing how TCR‐based immunotherapies can achieve broader dissemination through innovations in cell manufacturing and non‐viral genome integration techniques.

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Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers

Cited by 454 publications

References 33 publications

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

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

Deciphering the transcriptomic landscape of tumor-infiltrating CD8 lymphocytes in B16 melanoma tumors with single-cell RNA-Seq

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

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