Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
Sci Transl Med. 2021 May 5;13(592). doi: 10.1126/scitranslmed.abc3196.
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 (CD8NK1.1) revealed substantial up-regulation of granzymes, perforin, killer lectin-like receptors, and innate signaling molecules in comparison to CD8NK1.1 T cells. Adoptive transfer of CD8NK1.1 cells from previously exposed animals offered substantially enhanced protection and improved survival against melanoma tumors and influenza infection compared to CD8NK1.1 cells. Freshly isolated human CD8CD61 T cells exhibited heightened allogeneic killing activity in comparison to CD8CD61 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, CD8CD161, and CD8CD161 T cells transduced with a human epidermal growth factor receptor-2 (HER2)-specific CAR construct. In vitro, CD8CD161 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.
在人类中，自然杀伤 (NK) 细胞标志物 CD161 可识别 T 细胞的几个亚群，包括表达多克隆 CD8αβT 细胞受体、具有组织定位病毒特征特异性的亚群。该亚群还表现出增强的细胞毒性和记忆表型。在这里，我们对这个独特的 T 细胞亚群进行了表征，并确定了其在嵌合抗原受体 (CAR) T 细胞治疗中的潜在适用性。在小鼠中，CD161 等效 CD8 T 细胞群体 (CD8NK1.1) 之间的基因表达谱分析显示，与 CD8NK1.1 T 细胞相比，颗粒酶、穿孔素、杀伤细胞凝集素样受体和先天信号分子的表达显著上调。与 CD8NK1.1 细胞相比，从先前暴露的动物中过继转移 CD8NK1.1 细胞可显著增强对黑素瘤肿瘤和流感感染的保护和存活率。与 CD8CD61 T 细胞或总外周血单核细胞 (PBMC) 相比，新鲜分离的人 CD8CD61 T 细胞表现出更高的同种异体杀伤活性。为了确定该亚群是否可能提高针对实体瘤的 CAR T 细胞治疗的抗肿瘤疗效，我们比较了 bulk PBMCs、CD8CD161 和 CD8CD161 T 细胞转导的人表皮生长因子受体 2 (HER2)-特异性 CAR 构建体。在体外，CD8CD161 CAR 转导的 T 细胞更快、更有效地杀死 HER2 靶标。同样，这些细胞在 HER2 胰腺导管腺癌异种移植模型中介导了增强的体内抗肿瘤疗效，表现出颗粒酶的高表达和衰竭标志物的低表达。这些数据表明，该 T 细胞亚群为改善 CAR T 细胞治疗实体瘤提供了机会。
