英国弗朗西斯·克里克研究所Samra Turajlic、伦敦大学学院Sergio A. Quezada等研究人员合作揭示肾透明细胞癌抗PD-1反应和耐药性的决定因素。相关论文于2021年10月28日在线发表在《癌细胞》杂志上。

ADAPTeR是一项对15名治疗无效的转移性肾透明细胞癌（ccRCC）患者（115个多区域肿瘤样本）进行的nivolumab（抗PD-1）的前瞻性II期研究，目的是了解支撑治疗反应的机制。基因组分析显示肿瘤分子特征和反应之间没有相关性，而ccRCC特异性人类内源性逆转录病毒的表达与临床反应间接相关。T细胞受体（TCR）分析显示，应答者治疗前扩大的TCR克隆数量明显较多，表明预先存在免疫力。治疗后保持高度相似的TCR集群预示着反应，表明正在进行的抗原接触和可能识别相同抗原的T细胞家族的生存。

在应答者中，与nivolumab结合的CD8⁺T细胞被扩增并表达GZMK/B。这些数据表明，nivolumab同时驱动维持和替换以前扩增的T细胞克隆，但只有维持与反应相关。研究人员认为，维持和增强先前存在的反应是抗PD-1作用模式的一个关键因素。

附：英文原文

Title: Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

Author: Lewis Au, Emine Hatipoglu, Marc Robert de Massy, Kevin Litchfield, Gordon Beattie, Andrew Rowan, Desiree Schnidrig, Rachael Thompson, Fiona Byrne, Stuart Horswell, Nicos Fotiadis, Steve Hazell, David Nicol, Scott T.C. Shepherd, Annika Fendler, Robert Mason, Lyra Del Rosario, Kim Edmonds, Karla Lingard, Sarah Sarker, Mary Mangwende, Eleanor Carlyle, Jan Attig, Kroopa Joshi, Imran Uddin, Pablo D. Becker, Mariana Werner Sunderland, Ayse Akarca, Ignazio Puccio, William W. Yang, Tom Lund, Kim Dhillon, Marcos Duran Vasquez, Ehsan Ghorani, Hang Xu, Charlotte Spencer, José I. López, Anna Green, Ula Mahadeva, Elaine Borg, Miriam Mitchison, David A. Moore, Ian Proctor, Mary Falzon, Lisa Pickering, Andrew J.S. Furness, James L. Reading, Roberto Salgado, Teresa Marafioti, Mariam Jamal-Hanjani, Chris Abbosh, Kai-Keen Shiu, John Bridgewater, Daniel Hochhauser, Martin Forster, Siow-Ming Lee, Tanya Ahmad, Dionysis Papadatos-Pastos, Sam Janes, Peter Van Loo, Katey Enfield, Nicholas McGranahan, Ariana Huebner, Stephan Beck, Peter Parker, Henning Walczak, Tariq Enver, Rob Hynds, Ron Sinclair, Chi-wah Lok, Zoe Rhodes

Issue&Volume: 2021-10-28

Abstract: ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.

DOI: 10.1016/j.ccell.2021.10.001

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00543-2