Research ArticleCancer

A subset of cytotoxic effector memory T cells enhances CAR T cell efficacy in a model of pancreatic ductal adenocarcinoma

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Science Translational Medicine  05 May 2021:
Vol. 13, Issue 592, eabc3196
DOI: 10.1126/scitranslmed.abc3196

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High-efficiency CAR T cells

Advancements in chimeric antigen receptor (CAR) T cells have often been restricted to modifications to the CAR itself rather than the cells expressing the CAR. Here, Konduri et al. investigated the impact of using a unique population of T cells as a starting material instead of bulk T cells. The authors showed that a subset of effector memory T cells expressing the protein CD161 were highly cytotoxic and controlled tumor burden in a mouse model of melanoma. Transducing CD161-expressing T cells with a tumor antigen–specific CAR led to improved control of tumor burden in a mouse model of pancreatic cancer. Together, these findings suggest that selective use of this cytotoxic T cell population may improve CAR T cell therapies.

Abstract

In humans, the natural killer (NK) cell marker CD161 identifies several subsets of T cells, including a polyclonal CD8 αβ T cell receptor–expressing subset with characteristic specificity for tissue-localized viruses. This subset also displays enhanced cytotoxic and memory phenotypes. Here, we characterized this unique T cell subset and determined its potential suitability for use in chimeric antigen receptor (CAR) T cell therapy. In mice, gene expression profiling among the CD161-equivalent CD8+ T cell populations (CD8+NK1.1+) revealed substantial up-regulation of granzymes, perforin, killer lectin-like receptors, and innate signaling molecules in comparison to CD8+NK1.1 T cells. Adoptive transfer of CD8+NK1.1+ cells from previously exposed animals offered substantially enhanced protection and improved survival against melanoma tumors and influenza infection compared to CD8+NK1.1 cells. Freshly isolated human CD8+CD61+ T cells exhibited heightened allogeneic killing activity in comparison to CD8+CD61 T cells or total peripheral blood mononuclear cells (PBMCs). To determine whether this subset might improve the antitumor efficacy of CAR T cell therapy against solid tumors, we compared bulk PBMCs, CD8+CD161, and CD8+CD161+ T cells transduced with a human epidermal growth factor receptor-2 (HER2)–specific CAR construct. In vitro, CD8+CD161+ CAR-transduced T cells killed HER2+ targets faster and with greater efficiency. Similarly, these cells mediated enhanced in vivo antitumor efficacy in xenograft models of HER2+ pancreatic ductal adenocarcinoma, exhibiting elevated expression of granzymes and reduced expression of exhaustion markers. These data suggest that this T cell subset presents an opportunity to improve CAR T cell therapy for the treatment of solid tumors.

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