近日，英国伦敦大学学院教授Craig Dick及其课题组提出了非小细胞肺癌的亚克隆免疫逃避。该研究于2025年7月3日发表于国际一流学术期刊《癌细胞》杂志上。

该研究团队利用多区域TRACERx肺癌进化研究来生成一个患者来源的类器官- T细胞共培养平台，允许在单克隆分辨率下进行亚克隆免疫逃逸的功能分析。该团队从3例患者的11个不同肿瘤区域建立了类器官系，随后分离了81个单个克隆亚系。与肿瘤浸润淋巴细胞（TIL）或自然杀伤细胞（NK）共培养显示所有3例患者的肿瘤固有和亚克隆免疫逃逸。免疫逃避亚克隆代表了具有独特进化历史的遗传上不同的谱系。这表明在同一肿瘤中可以分离出免疫逃避亚克隆和非逃避亚克隆，提示肿瘤亚克隆进化直接影响免疫逃避。

据介绍，癌症很少对免疫疗法有完全的反应。虽然肿瘤由多个遗传上不同的克隆组成，但由于无法从人类癌症中分离和繁殖单个亚克隆，这是否会影响免疫逃逸的潜力仍不清楚。

附：英文原文

Title: Subclonal immune evasion in non-small cell lung cancer

Author: Krijn K. Dijkstra, Roberto Vendramin, Despoina Karagianni, Maartje Witsen, Felipe Gálvez-Cancino, Mark S. Hill, Kane A. Foster, Vittorio Barbè, Mihaela Angelova, Robert E. Hynds, David R. Pearce, Carlos Martínez-Ruiz, James R.M. Black, Ariana Huebner, Oriol Pich, Andrew Rowan, Marcellus Augustine, Clare Puttick, David A. Moore, Lydia L. Liu, Sadegh Saghafinia, Joris van de Haar, Selvaraju Veeriah, Cristina Naceur-Lombardelli, Antonia Toncheva, Supreet Kaur Bola, Crispin T. Hiley, Mariam Jamal-Hanjani, Nicholas McGranahan, Kevin Litchfield, James L. Reading, Benny Chain, Abigail Bunkum, Adam Atkin, Aiman Alzetani, Akshay J. Patel, Alan Kirk, Alexander James Procter, Alexander M. Frankell, Alexandra Rice, Allan Hackshaw, Amrita Bajaj, Anand Devaraj, Anca Grapa, Andrew G. Nicholson, Andrew Kidd, Andrew Rowan, Angela Dwornik, Angela Leek, Angeliki Karamani, Anne-Marie Hacker, Anshuman Chaturvedi, Antonio Paiva-Correia, Aoife Walker, Apostolos Nakas, Ariana Huebner, Arjun Nair, Asia Ahmed, Aya Osman, Azmina Sodha-Ramdeen, Babu Naidu, Benny Chain, Camilla Pilotti, Carla Castignani, Carlos Martínez-Ruiz, Caroline Dive, Catarina Veiga, Charles Swanton, Charles-Antoine Collins-Fekete, Chiara Proli, Chris Bailey, Cian Murphy, Claire Wilson, Clare E. Weeden, Clare Puttick, Claudia Lee, Colin R. Lindsay, Corentin Richard, Craig Dick

Issue&Volume: 2025-07-03

Abstract: Cancers rarely respond completely to immunotherapy. While tumors consist of multiple genetically distinct clones, whether this affects the potential for immune escape remains unclear due to an inability to isolate and propagate individual subclones from human cancers. Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived organoid – T cell co-culture platform that allows the functional analysis of subclonal immune escape at single clone resolution. We establish organoid lines from 11 separate tumor regions from three patients, followed by isolation of 81 individual clonal sublines. Co-culture with tumor infiltrating lymphocytes (TIL) or natural killer (NK) cells reveals cancer-intrinsic and subclonal immune escape in all 3 patients. Immune evading subclones represent genetically distinct lineages with a unique evolutionary history. This indicates that immune evading and non-evading subclones can be isolated from the same tumor, suggesting that subclonal tumor evolution directly affects immune escape.

DOI: 10.1016/j.ccell.2025.06.012

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00262-4