PD-1阻断后肿瘤特异性T细胞的克隆替换（NatMed,IF：30.641）

PD-1阻断后肿瘤特异性T细胞的克隆替换（NatMed,IF：

30.641）

SCI

16 August 2019

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

•Yost KE, Satpathy AT, Wells DK, et al. Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat Med 2019;25:1251-9.

•Corresponding author:Ansuman T. Satpathy, Anne Lynn S. Chang and Howard Y. Chang, Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA. Department of Dermatology, Stanford University School of Medicine,RedwoodCity,CA,USA.E-mail:*********************; *********************;*********************

Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer. 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 unclear2–4. 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.

阻断T细胞上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，仍然不清楚T细胞对检查点阻断的反应，是否依赖于先前存在的肿瘤浸润淋巴细胞的再激活或新T细胞的募集。在这里，我们对来自抗PD-1治疗前后基底细胞癌或鳞状细胞癌患者的79046个细胞进行了成对的单细胞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细胞功能障碍的偶联，其特征在于CD8 + CD39 + 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源于先前已存在的肿瘤浸润性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CD8+T细胞衰竭的患者中优先观察到T细胞的克隆替换，并且在患有基底或鳞状细胞癌的患者中较明显。这些结果表明，先前存在的肿瘤特异性T细胞可能具有有限的再生能力，并且T细胞对检查点阻断的反应来自可能刚刚进入肿瘤不久的一系列不同的T细胞克隆库。

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