Prevalent and Diverse Intratumoral Oncoprotein-Specific CD8+ T Cells within Polyomavirus-Driven Merkel Cell Carcinomas
Prevalent and Diverse Intratumoral Oncoprotein-Specific CD8+ T Cells within Polyomavirus-Driven Merkel Cell Carcinomas
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DOI：
10.1158/2326-6066.cir-19-0647
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发表时间：
2020-05-01
影响因子：
10.1
通讯作者：
Koelle, David M.
中科院分区：
文献类型：
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作者：
Jing, Lichen;Ott, Mariliis;Koelle, David M.
默克尔细胞癌 (MCC) 通常是由默克尔细胞多瘤病毒 (MCPyV) T 抗原 (T-Ag) 持续表达引起的。这些非自身蛋白包含约 400 个氨基酸 (AA)。约一半患者对免疫检查点抑制剂的临床反应可能与 T-Ag 特异性 T 细胞有关。增加 CD8(+) T 细胞数量、宽度或功能的策略可以增强检查点抑制，但增强免疫力的疫苗必须避免传递致癌 T 抗原结构域。我们用人工抗原呈递细胞 (aAPC) 系统探测了 MCC 肿瘤浸润淋巴细胞 (TIL)，并证实了合成肽、HLA 肽四聚体和树突状细胞 (DC) 对 T-Ag 的识别。 12 名受试者中有 9 名 (75%) 的 TIL 含有识别每人 1-8 个 MCPyV 表位的 CD8(+) T 细胞。对 16 个 MCPyV CD8(+) TIL 表位和先前 TIL 数据的分析表明，97% 的 MCPyV+ MCC 患者具有 HLA 等位基因，该等位基因具有限制 CD8(+) T 细胞对 MCPyV T-Ag 反应的遗传潜力。 LT AA 70-110 区域富含表位，而 T-Ag 的致癌结构域并未得到普遍认可。记录了表达 T-Ag 的 DC 的特异性识别。从大多数肿瘤中回收 MCPyV 癌蛋白特异性 CD8(+) TIL 表明抗原冷漠不太可能是检查点抑制失败的主要原因。受不同 HLA 等位基因限制的无数表位表明，如果可以克服肿瘤免疫抑制，并且可以在不影响免疫原性的情况下修饰 T-Ag 的致癌区域，那么疫苗接种可以成为免疫治疗的合理组成部分。
Merkel cell carcinoma (MCC) is often caused by persistent expression of Merkel cell polyomavirus (MCPyV) T-antigen (T-Ag). These non-self proteins comprise about 400 amino acids (AA). Clinical responses to immune checkpoint inhibitors, seen in about half of patients, may relate to T-Ag-specific T cells. Strategies to increase CD8(+) T-cell number, breadth, or function could augment checkpoint inhibition, but vaccines to augment immunity must avoid delivery of oncogenic T-antigen domains. We probed MCC tumor-infiltrating lymphocytes (TIL) with an artificial antigen-presenting cell (aAPC) system and confirmed T-Ag recognition with synthetic peptides, HLA-peptide tetramers, and dendritic cells (DC). TILs from 9 of 12 (75%) subjects contained CD8(+) T cells recognizing 1-8 MCPyV epitopes per person. Analysis of 16 MCPyV CD8(+) TIL epitopes and prior TIL data indicated that 97% of patients with MCPyV+ MCC had HLA alleles with the genetic potential that restrict CD8(+) T-cell responses to MCPyV T-Ag. The LT AA 70-110 region was epitope rich, whereas the oncogenic domains of T-Ag were not commonly recognized. Specific recognition of T-Ag-expressing DCs was documented. Recovery of MCPyV oncoprotein-specific CD8(+) TILs from most tumors indicated that antigen indifference was unlikely to be a major cause of checkpoint inhibition failure. The myriad of epitopes restricted by diverse HLA alleles indicates that vaccination can be a rational component of immunotherapy if tumor immune suppression can be overcome, and the oncogenic regions of T-Ag can be modified without impacting immunogenicity.