Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors

Duhen, Thomas; Duhen, Rebekka; Montler, Ryan; Moses, Jake; Moudgil, Tarsem; Miranda, Noel F C C de; Goodall, Cheri P.; Blair, Tiffany C.; Fox, Bernard A.; McDermott, Jason; Chang, Shu Ching; Grunkemeier, Gary L.; Leidner, Rom S.; Bell, R. Bryan; Weinberg, Andrew D.

doi:10.1038/s41467-018-05072-0

Cited by 670 publications

(801 citation statements)

References 52 publications

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“…We first examined the proportion of a CD39 + CD103 + CD8 + TIL subset representing tumor reactivity . The 4‐1BB pos PD‐1 high subpopulation showed the highest percentages of CD39 + CD103 + cells among both total and NY‐ESO‐1 157‐165 –specific CD8 + TILs, followed by the 4‐1BB neg PD‐1 high and PD‐1 int subpopulations (Fig.…”

Section: Resultsmentioning

confidence: 99%

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: Resultsmentioning

confidence: 99%

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

et al. 2019

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“…Elucidating patient-specific private neoantigens in a manner that is at once rapid, scalable, and costeffective represents an unprecedented challenge. 215 Pre-clinical data suggests that preparative sorting of TIL or PBMC based on expression of co-inhibitory markers (PD1, TIM3, CD39) 159,207,216,217 or acute activation markers (CD134, CD137) 162,207,216 can enrich for neoantigen-specific T cells. ACT of TIL enriched for private neoantigen reactivity has resulted in durable CRs in a subset of patients with common solid cancers, including those arising from the bile duct, breast, and cervix.…”

Section: Public and Private Cancer Neoantigensmentioning

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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“…First, although the TME contained a rich diversity of T cell phenotypes, including several CD4 + T helper subtypes and a spectrum of CD8 + activation and dysfunction phenotypes, clonally-expanded cells post-therapy were highly-enriched in CD8 + T cells that were phenotypically exhausted. 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 .…”

Section: Discussionmentioning

confidence: 86%

“…2d). This analysis identified an exhaustion-specific gene expression module containing known exhaustion markers (HAVCR3, TIGIT), tissue resident memory T cell (Trm) markers (ITGAE, CXCR6) 35,36 , and the extracellular ATPase CD39 (ENTPD1), which has been shown to identify CD8 + TILs that recognize tumor antigens 13,[37][38][39] . The high levels of PDCD1 (PD-1) 40 , presence of ITGAE (CD103) and lack of KLRG1 13,37-39 in exhausted clusters also supported an enrichment of tumor-specific T cells in this population.…”

Section: Resultsmentioning

confidence: 99%

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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Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors

Cited by 670 publications

References 52 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

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

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

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