小柯机器人

美国纽约纪念斯隆凯特琳癌症中心Benjamin D. Greenbaum，Taha Merghoub和Roberta Zappasodi共同合作取得重要工作进展。他们研究发现基本的免疫和致癌性权衡决定了驱动因子的突变和适合度。该项研究成果2022年5月11日在线发表于《自然》杂志上。

研究人员提出了一个统一的理论“自由适应度”框架，该框架将多模式基因组、表观遗传学、转录组学和蛋白质组学数据整合到驱动基因突变赋予癌细胞适应度优势的限速过程的生物物理模型中。研究人员专注于癌症中突变最多的基因TP53，提出了突变p53浓度的推断，并证明TP53热点突变最佳地解决了致癌潜力和新抗原免疫原性之间的进化权衡。他们的模型预测癌症基因组图谱中的患者存活率和接受免疫疗法治疗的肺癌患者以及TP53变异种系携带者的肿瘤发病年龄。热点突变之间预测的差异免疫原性在癌症患者和健康个体的独特大型数据集中进行了实验验证。

他们的数据表明，对TP53突变的免疫选择性压力在非癌性病变中的作用比在肿瘤中的作用小，这表明靶向免疫疗法可能为前者提供早期预防机会。因此，确定免疫原性和致癌功能对热点突变选择性优势的相对贡献对于精准免疫疗法和对肿瘤进化的理解都具有重要意义。

据了解，癌症中的错义驱动突变集中在几个热点。已经提出了多种机制来解释这种偏差，包括偏向突变过程、表型差异和新抗原的免疫编辑。然而，目前还没有一个模型可以衡量这些特征对肿瘤进化的相对贡献。

附：英文原文

Title: Fundamental immune–oncogenicity trade-offs define driver mutation fitness

Author: Hoyos, David, Zappasodi, Roberta, Schulze, Isabell, Sethna, Zachary, de Andrade, Kelvin Csar, Bajorin, Dean F., Bandlamundi, Chaitanya, Callahan, Margaret K., Funt, Samuel A., Hadrup, Sine R., Holm, Jeppe S., Rosenberg, Jonathan E., Shah, Sohrab P., Vzquez-Garca, Ignacio, Weigelt, Britta, Wu, Michelle, Zamarin, Dmitriy, Campitelli, Laura F., Osborne, Edward J., Klinger, Mark, Robins, Harlan S., Khincha, Payal P., Savage, Sharon A., Balachandran, Vinod P., Wolchok, Jedd D., Hellmann, Matthew D., Merghoub, Taha, Levine, Arnold J., uksza, Marta, Greenbaum, Benjamin D.

Issue&Volume: 2022-05-11

Abstract: Missense driver mutations in cancer are concentrated in a few hotspots1. Various mechanisms have been proposed to explain this skew, including biased mutational processes2, phenotypic differences3,4,5,6 and immunoediting of neoantigens7,8; however, to our knowledge, no existing model weighs the relative contribution of these features to tumour evolution. We propose a unified theoretical ‘free fitness’ framework that parsimoniously integrates multimodal genomic, epigenetic, transcriptomic and proteomic data into a biophysical model of the rate-limiting processes underlying the fitness advantage conferred on cancer cells by driver gene mutations. Focusing on TP53, the most mutated gene in cancer1, we present an inference of mutant p53 concentration and demonstrate that TP53 hotspot mutations optimally solve an evolutionary trade-off between oncogenic potential and neoantigen immunogenicity. Our model anticipates patient survival in The Cancer Genome Atlas and patients with lung cancer treated with immunotherapy as well as the age of tumour onset in germline carriers of TP53 variants. The predicted differential immunogenicity between hotspot mutations was validated experimentally in patients with cancer and in a unique large dataset of healthy individuals. Our data indicate that immune selective pressure on TP53 mutations has a smaller role in non-cancerous lesions than in tumours, suggesting that targeted immunotherapy may offer an early prophylactic opportunity for the former. Determining the relative contribution of immunogenicity and oncogenic function to the selective advantage of hotspot mutations thus has important implications for both precision immunotherapies and our understanding of tumour evolution.

DOI: 10.1038/s41586-022-04696-z

Source: https://www.nature.com/articles/s41586-022-04696-z

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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