Studies have characterized the immune escape landscape across primary tumors. However, whether late-stage metastatic tumors present differences in genetic immune escape (GIE) prevalence and dynamics remains unclear. We performed a pan-cancer characterization of GIE prevalence across six immune escape pathways in 6,319 uniformly processed tumor samples. To address the complexity of the HLA-I locus in the germline and in tumors, we developed LILAC, an open-source integrative framework. One in four tumors harbors GIE alterations, with high mechanistic and frequency variability across cancer types. GIE prevalence is generally consistent between primary and metastatic tumors. We reveal that GIE alterations are selected for in tumor evolution and focal loss of heterozygosity of HLA-I tends to eliminate the HLA allele, presenting the largest neoepitope repertoire. Finally, high mutational burden tumors showed a tendency toward focal loss of heterozygosity of HLA-I as the immune evasion mechanism, whereas, in hypermutated tumors, other immune evasion strategies prevail.

研究描述了原发性肿瘤的免疫逃逸情况。然而，晚期转移性肿瘤在遗传免疫逃逸（GIE）患病率和动态方面是否存在差异仍不清楚。我们对 6,319 个经过统一处理的肿瘤样本中的 6 个免疫逃逸途径的 GIE 患病率进行了泛癌表征。为了解决生殖系和肿瘤中 HLA-I 位点的复杂性，我们开发了 LILAC，一个开源综合框架。四分之一的肿瘤存在 GIE 改变，不同癌症类型的机制和频率变异性较高。原发性肿瘤和转移性肿瘤之间的 GIE 患病率通常一致。我们发现，GIE 改变是在肿瘤进化中选择的，而HLA-I杂合性的局灶性丢失往往会消除 HLA 等位基因，从而呈现出最大的新表位库。最后，高突变负荷肿瘤显示出HLA-I杂合性局灶性丧失作为免疫逃避机制的趋势，而在高突变肿瘤中，其他免疫逃避策略占主导地位。