Mutation Rate Evolution Drives Immune Escape In Mismatch Repair-Deficient Cancer
Mutation Rate Evolution Drives Immune Escape In Mismatch Repair-Deficient Cancer
复制标题
突变率进化驱动错配修复缺陷癌症的免疫逃逸
DOI：
10.1101/2022.03.06.482973
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Kayhanian H
中科院分区：
文献类型：
--
作者：
Kayhanian H
突变率优化驱动进化和免疫逃避细菌和慢病毒株，包括艾滋病毒。进化的癌症谱系是否同样适应突变率以增加肿瘤细胞的适应性尚不清楚。在这里，通过绘制错配修复缺陷（MMRd）结肠直肠癌的克隆图谱，我们发现基因组MMRd易变性与新抗原选择共同进化，驱动肿瘤内多样化和免疫逃逸。在机制上，我们发现微卫星不稳定性通过随机移码开关，通过切换错配修复基因MSH6和MSH3（分别为C8和A8）中的两个超可变单核苷酸同聚体来调节亚克隆DNA修复。这些可进化性开关的自发突变和逆转调节了MMRd癌症进化过程中的亚克隆突变率、突变偏倚和克隆HLA多样性。实验和模拟相结合的研究表明，亚克隆免疫选择倾向于增加MMR突变。因此，MMRd癌症通过使亚克隆突变率和突变偏倚适应免疫选择，从而加剧了肿瘤内的异质性，揭示了新抗原选择和适应性基因组突变之间保守的共同进化军备竞赛。我们的工作揭示了以前隐藏在批量分析中的MMRd癌症进化中的突变复杂性和微卫星生物学层。
Mutation rate optimisation drives evolution and immune evasion of bacteria and lentiviral strains, including HIV. Whether evolving cancer lineages similarly adapt mutation rates to increase tumour cell fitness is unknown. Here, by mapping the clonal topography of mismatch repair-deficient (MMRd) colorectal cancer, we show that genomic MMRd mutability co-evolves with neoantigen selection to drive intratumour diversification and immune escape. Mechanistically, we find that microsatellite instability modulates subclonal DNA repair by toggling two hypermutable mononucleotide homopolymer runs in the mismatch repair genes MSH6 and MSH3 (C8 and A8, respectively) through stochastic frameshift switching. Spontaneous mutation and reversion at these evolvability switches modulates subclonal mutation rate, mutation bias, and clonal HLA diversity during MMRd cancer evolution. Combined experimental and simulation studies demonstrate that subclonal immune selection favours incremental MMR mutations. MMRd cancers thus fuel intratumour heterogeneity by adapting subclonal mutation rate and mutation bias to immune selection, revealing a conserved co-evolutionary arms race between neoantigen selection and adaptive genomic mutability. Our work reveals layers of mutational complexity and microsatellite biology in MMRd cancer evolution previously hidden in bulk analyses.
影响因子：
4.6
作者：
Molnar C;Jermyn IH;Kato Z;Rahkama V;Östling P;Mikkonen P;Pietiäinen V;Horvath P
通讯作者：
Horvath P
dN/dS 动力学量化肿瘤免疫原性并预测对免疫治疗的反应
DOI：
--
发表时间：
2020
期刊：
bioRxiv
影响因子：
--
作者：
L. Zapata;G. Caravagna;Marc J. Williams;E. Lakatos;K. AbdulJabbar;B. Werner;T. Graham;A. Sottoriva
通讯作者：
A. Sottoriva