小柯机器人

英国癌症研究所Andrea Sottoriva、Trevor A. Graham和Luis Zapata研究团队合作在研究中取得进展。他们的研究发现免疫选择决定肿瘤抗原性并影响其对检查点抑制剂的反应。2023年3月9日出版的《自然-遗传学》杂志发表了这项成果。

研究人员使用免疫dN/dS（免疫肽中非同义突变与同义突变的比例）分析了10,000个原发性肿瘤和356个免疫检查点治疗后的转移肿瘤，以测量整体和个体的免疫选择。当抗原突变被阴性选择去除时，研究人员将肿瘤归类为免疫编辑；当抗原性被异常免疫调节掩盖时，研究人员将肿瘤归类为免疫逃逸。只有在免疫编辑的肿瘤中，免疫捕获与CD8 T细胞浸润有关。免疫逃逸的转移瘤对免疫治疗的反应最好，而免疫编辑的患者则没有受益，这表明预先存在耐药机制。

同样，在纵向队列中，纳武利尤单抗治疗仅去除非免疫编辑患者免疫肽层中的新抗原，该组的总体生存反应最优。该研究使用dN/dS来区分免疫编辑和免疫逃逸的肿瘤，测量潜在的抗原性并最终帮助预测患者对治疗的反应。

研究人员表示，在癌症中，进化压力选择了能逃避免疫系统的克隆。

附：英文原文

Title: Immune selection determines tumor antigenicity and influences response to checkpoint inhibitors

Author: Zapata, Luis, Caravagna, Giulio, Williams, Marc J., Lakatos, Eszter, AbdulJabbar, Khalid, Werner, Benjamin, Chowell, Diego, James, Chela, Gourmet, Lucie, Milite, Salvatore, Acar, Ahmet, Riaz, Nadeem, Chan, Timothy A., Graham, Trevor A., Sottoriva, Andrea

Issue&Volume: 2023-03-09

Abstract: In cancer, evolutionary forces select for clones that evade the immune system. Here we analyzed >10,000 primary tumors and 356 immune-checkpoint-treated metastases using immune dN/dS, the ratio of nonsynonymous to synonymous mutations in the immunopeptidome, to measure immune selection in cohorts and individuals. We classified tumors as immune edited when antigenic mutations were removed by negative selection and immune escaped when antigenicity was covered up by aberrant immune modulation. Only in immune-edited tumors was immune predation linked to CD8 T cell infiltration. Immune-escaped metastases experienced the best response to immunotherapy, whereas immune-edited patients did not benefit, suggesting a preexisting resistance mechanism. Similarly, in a longitudinal cohort, nivolumab treatment removes neoantigens exclusively in the immunopeptidome of nonimmune-edited patients, the group with the best overall survival response. Our work uses dN/dS to differentiate between immune-edited and immune-escaped tumors, measuring potential antigenicity and ultimately helping predict response to treatment.

DOI: 10.1038/s41588-023-01313-1

Source: https://www.nature.com/articles/s41588-023-01313-1

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex