针对中国人群中HPV阳性宫颈癌的T细胞治疗靶点发现及其靶向治疗研究

Cervical cancer is the most common female genital malignancy, and most patients with cervical cancer are HPV positive. For patients with recurrent or metastatic advanced cervical cancer, the efficacy of existing treatments such as radiotherapy and chemotherapy is very limited. Recently, treatment of tumors with TCR-T cells against HPV has made significant progress in clinic. The target recognized by TCR is “peptide-HLA complex”. The existing research only focused on HLA-A0201 which is the most popular subtype in Western, while only 10% of the Chinese population express this HLA subtype. However, HLA-A1101/A2402, which is more widely distributed in Chinese population (70% Chinese express these subtypes), lacks basic research, which fundamentally limits the development of subsequent TCR-T cell therapy products. Applicant's previous studies have initially identified several new A1101 restricted HPV peptides that function to activate T cells in vitro..This project aims to further identify HLA-A1101/A2402 restricted HPV E6/E7 peptides, use these peptides as targets for TCR-T treatment of cervical cancer, and to validate the feasibility of peptide-specific TCR-T cells to treat cervical cancer in preclinical levels. This project will provide new ideas for the treatment of clinical HPV-positive advanced cervical cancer, which will greatly help China's cervical cancer precision treatment and new drug development industry.

宫颈癌是最常见的女性生殖道恶性肿瘤，且大部分宫颈癌患者为HPV阳性。传统放化疗对于复发或转移性晚期宫颈癌效果有限。近年来针对HPV的TCR-T细胞治疗肿瘤已经在临床实践中取得显著进展。T细胞识别的靶点是“抗原短肽-HLA复合物”，现有研究只针对西方人较多的HLA-A0201亚型人群，而中国人群中仅10%表达这种HLA亚型；针对中国人群中分布较多的HLA-A1101/A2402型（占中国人群的70%）缺乏基础研究，这也从根本上限制了后续TCR-T细胞治疗产品的开发。申请人实验室通过前期研究，已经初步发现若干新的A1101递呈的HPV相关短肽序列，这些短肽具备激活T细胞的功能。.本项目拟针对中国人的主要HLA亚型，①寻找并优化HPV蛋白相关抗原肽（新靶点）②筛选HPV特异性的T细胞克隆③在动物水平验证靶向新靶点的TCR-T治疗宫颈癌的有效性。本项目将为临床HPV阳性晚期宫颈癌的治疗提供新思路。

宫颈癌是最常见的女性生殖道恶性肿瘤，且大部分宫颈癌患者均为HPV阳性。对于复发或转移性晚期宫颈癌，放化疗效果有限。近年来针对恶性肿瘤的细胞免疫治疗兴起，T细胞治疗有望成为晚期宫颈癌的有效治疗手段。目前针对中国人群中分布较多的HLA-A1101分型缺乏可靠的HPV相关靶点，这也限制了相应的T细胞靶向治疗产品的开发。在本项目实施过程中，我们发现了两个新的HLA-A1101限制性的CD8 T细胞治疗靶点，分别为E693-101（TTLEQQYNK, TTL）和E789-97（IVCPICSQK, IVC）。并针对这两个靶点筛选了若干亲和力高、特异性好的TCR。我们对TTL和IVC的TCR-pMHC相互作用的关键位点进行了分析，结果显示“xxLEQxYNK”和 “xVxPIxxxK”分别为二者的保守基序。将TTL和IVC特异性的高亲和力TCR制备TCR-T，并进行功能验证。体外和体内功能显示这些TCR可以识别并杀伤表达HPV和HLA-A*11:01的肿瘤细胞。同时TTL和IVC特异性的TCR-T还可以识别并杀伤HPV阳性的宫颈癌类器官模型。这显示本项目发现的短肽和TCR具备潜在的临床应用价值，可以用于后续的宫颈癌免疫治疗。