Konduri et al. showed that CD3+CD8+NK1.1+ cells represent a subset of CD8+ T cells with enhanced cytotoxicity, and their adoptive transfer from previously exposed animals provided protection against influenza infection and melanoma tumors in mice. Human CD8+CD161+ cell populations were phenotypically similar to murine CD8+NK1.1+ cells and showed enhanced TCR-mediated cytolytic capabilities. Compared to CD8+CD161- or bulk PBMC HER2CAR-transduced T cells, CD8+CD161+ HER2CAR T cells showed enhanced killing, improved survival, and reduced exhaustion, leading to complete tumor eradication in HER2+ tumor models.
Contributed by Shishir Pant
ABSTRACT: In humans, the natural killer (NK) cell marker CD161 identifies several subsets of T cells, including a polyclonal CD8 __ 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.
Author Info: (1) Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. (2) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030,
Author Info: (1) Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. (2) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Houston, TX 77030, USA. (3) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Houston, TX 77030, USA. (4) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Houston, TX 77030, USA. (5) Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. (6) Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. (7) Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. (8) Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA. (9) Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA. (10) Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. (11) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Houston, TX 77030, USA. (12) Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. (13) Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. (14) Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. (15) Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. (16) Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. Scott Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA. (17) Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Michael E. DeBakey VA Medical Center, Center for Translational Research on Inflammatory Diseases (CTRID), Houston, TX 77030, USA. (18) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (19) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (20) Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. decker@bcm.edu. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
