美国斯坦福大学医学院Howard Y. Chang研究组和Anne Lynn S. Chang研究组等合作发现PD-1阻断后肿瘤特异性T细胞的克隆替换。该研究于2019年8月发表于国际一流学术期刊《自然—医学》上。

研究人员对来自抗PD-1治疗前后基底或鳞状细胞癌患者位点匹配肿瘤的79046个细胞，进行了对应的单细胞RNA和T细胞受体测序。追踪T细胞受体克隆和转录表型揭示了肿瘤识别、克隆扩增和T细胞功能障碍的关联，其特征在于CD8和CD39双阳性T细胞的克隆扩增，其共表达慢性T细胞活化和衰竭的标志物。然而，T细胞克隆的扩增并非来自预先存在的肿瘤浸润性T淋巴细胞； 相反，扩增的克隆由先前在相同肿瘤中未观察到的新型克隆型组成。在衰竭的CD8阳性T细胞中优先观察到T细胞的克隆替代，并且在患有基底或鳞状细胞癌的患者中明显。这些结果表明，预先存在的肿瘤特异性T细胞可能具有有限的恢复能力，并且T细胞对检查点阻断的反应可能来自于刚刚进入肿瘤的不同T细胞克隆库。

据了解，阻断T细胞抑制性检查点受体的免疫疗法已经改变了癌症患者的临床护理。 然而，T细胞对检查点阻断的反应是否依赖于预先存在的肿瘤浸润淋巴细胞的再激活或新T细胞的募集尚不清楚。

附：英文原文

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

Author: Kathryn E. Yost, Ansuman T. Satpathy, Daniel K. Wells, Yanyan Qi, Chunlin Wang, Robin Kageyama, Katherine L. McNamara, Jeffrey M. Granja, Kavita Y. Sarin, Ryanne A. Brown, Rohit K. Gupta, Christina Curtis, Samantha L. Bucktrout, Mark M. Davis, Anne Lynn S. Chang, Howard Y. Chang

Issue&Volume: Volume 25 Issue 8, August 2019

Abstract: Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer1. However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor-infiltrating lymphocytes or on recruitment of novel T cells remains unclear24. Here we performed paired single-cell RNA and T cell receptor sequencing on 79,046 cells from site-matched tumors from patients with basal or squamous cell carcinoma before and after anti-PD-1 therapy. Tracking T cell receptor clones and transcriptional phenotypes revealed coupling of tumor recognition, clonal expansion and T cell dysfunction marked by clonal expansion of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, the expansion of T cell clones did not derive from pre-existing tumor-infiltrating T lymphocytes; instead, the expanded clones consisted of novel clonotypes that had not previously been observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells and evident in patients with basal or squamous cell carcinoma. These results demonstrate that pre-existing tumor-specific T cells may have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumor.

DOI: 10.1038/s41591-019-0522-3

Source:https://www.nature.com/articles/s41591-019-0522-3