美国国立卫生研究院Steven A. Rosenberg、Frank J. Lowery、Sri Krishna小组取得一项新突破。他们揭示了人转移性癌症中抗肿瘤新抗原反应性T细胞的分子特征。2022年2月3日出版的《科学》发表了这项成果。

通过将10个转移性人类肿瘤的55个新抗原特异性T细胞受体(TCR)克隆型(NeoTCR)映射到它们的单细胞转录组，研究人员确定了CD8⁺和CD4⁺新抗原反应性肿瘤浸润淋巴细胞(TIL)的特征。新抗原特异性TIL表现出肿瘤特异性扩增和功能失调表型，与血液迁移旁观者和调节性TIL不同。

对73个NeoTCR特征衍生克隆型的前瞻性预测和测试表明，一半的TCR可识别肿瘤抗原或自体肿瘤。NeoTCR特征可鉴别出靶向新抗原和非突变病毒或肿瘤相关抗原的TCR，具有常见的转移性TIL耗竭程序。NeoTCR特征描述了TIL在转移性肿瘤中的分布情况，可完全基于TIL转录组状态成功识别TCR，用于癌症免疫治疗。

据悉，准确鉴定抗肿瘤TCR是癌症细胞免疫疗法面临的重大挑战。

附：英文原文

Title: Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers

Author: Frank J. Lowery, Sri Krishna, Rami Yossef, Neilesh B. Parikh, Praveen D. Chatani, Nikolaos Zacharakis, Maria R. Parkhurst, Noam Levin, Sivasish Sindiri, Abraham Sachs, Kyle J. Hitscherich, Zhiya Yu, Nolan R. Vale, Yong-Chen Lu, Zhili Zheng, Li Jia, Jared J. Gartner, Victoria K. Hill, Amy R. Copeland, Shirley K. Nah, Robert V. Masi, Billel Gasmi, Scott Kivitz, Biman C. Paria, Maria Florentin, Sanghyun P. Kim, Ken-ichi Hanada, Yong F. Li, Lien T. Ngo, Satyajit Ray, Mackenzie L. Shindorf, Shoshana T. Levi, Ryan Shepherd, Chris Toy, Anup Y. Parikh, Todd D. Prickett, Michael C. Kelly, Rachel Beyer, Stephanie L. Goff, James C. Yang, Paul F. Robbins, Steven A. Rosenberg

Issue&Volume: 2022-02-03

Abstract: The accurate identification of antitumor T cell receptors (TCRs) represents a major challenge for the engineering of cell-based cancer immunotherapies. By mapping 55 neoantigen-specific TCR clonotypes (NeoTCRs) from 10 metastatic human tumors to their single-cell transcriptomes, we identified signatures of CD8+ and CD4+ neoantigen-reactive tumor-infiltrating lymphocytes (TILs). Neoantigen-specific TILs exhibited tumor-specific expansion with dysfunctional phenotypes, distinct from blood-emigrant bystanders and regulatory TILs. Prospective prediction and testing of 73 NeoTCR signature–derived clonotypes demonstrated that half of the tested TCRs recognized tumor antigens or autologous tumors. NeoTCR signatures identified TCRs that target driver neoantigens and nonmutated viral or tumor-associated antigens, suggesting a common metastatic TIL exhaustion program. NeoTCR signatures delineate the landscape of TILs across metastatic tumors, enabling successful TCR prediction based purely on TIL transcriptomic states for use in cancer immunotherapy.

DOI: abl5447

Source: https://www.science.org/doi/10.1126/science.abl5447