英国伦敦大学玛丽皇后学院Trevor A. Graham和英国癌症研究所Andrea Sottoriva小组合作取得一项新突破。他们揭示了肿瘤生长过程中新抗原的进化动力学。相关论文于2020年9月14日发表于《自然-遗传学》。

在本研究中，研究人员建立了新抗原进化的数学模型来确定负选择如何重塑正在生长癌症内新抗原的克隆性。该模型预测在没有免疫逃逸情况下，肿瘤新抗原要么是克隆产生的要么是低频发生的。超突变的肿瘤只有在免疫逃逸进化后才能建立。

此外,随着负选择强度的增加，负选择情况下体细胞突变的位点频谱看起来更加中性，这与经典的中性理论是一致的。通过对879例结肠癌、胃癌和子宫内膜癌患者的外显子组中新抗原频率和免疫逃逸以及RNA测序数据的分析也证实了这些预测。

据悉，癌症积累会导致新抗原的突变，这些新抗原会引发免疫反应，因此需要进行进化选择。

附：英文原文

Title: Evolutionary dynamics of neoantigens in growing tumors

Author: Eszter Lakatos, Marc J. Williams, Ryan O. Schenck, William C. H. Cross, Jacob Househam, Luis Zapata, Benjamin Werner, Chandler Gatenbee, Mark Robertson-Tessi, Chris P. Barnes, Alexander R. A. Anderson, Andrea Sottoriva, Trevor A. Graham

Issue&Volume: 2020-09-14

Abstract: Cancers accumulate mutations that lead to neoantigens, novel peptides that elicit an immune response, and consequently undergo evolutionary selection. Here we establish how negative selection shapes the clonality of neoantigens in a growing cancer by constructing a mathematical model of neoantigen evolution. The model predicts that, without immune escape, tumor neoantigens are either clonal or at low frequency; hypermutated tumors can only establish after the evolution of immune escape. Moreover, the site frequency spectrum of somatic variants under negative selection appears more neutral as the strength of negative selection increases, which is consistent with classical neutral theory. These predictions are corroborated by the analysis of neoantigen frequencies and immune escape in exome and RNA sequencing data from 879 colon, stomach and endometrial cancers. Mathematical modeling of evolutionary dynamics of neoantigens and immune escape in growing tumors shows that strong negative selection for neoantigens inhibits tumor growth but also provides a strong selective pressure for the evolution of immune escape.

DOI: 10.1038/s41588-020-0687-1

Source: https://www.nature.com/articles/s41588-020-0687-1