![]() This extensive polymorphism hampers the identification of tumor-specific somatic alterations, prompting the development of tools that specifically identify LOH of HLA-I (ref. One of the main challenges to perform such analyses lies in the extraordinary diversity of the HLA-I locus, with >15,000 different sequences of the HLA-A, HLA-B and HLA-C genes reported to date 11. In addition, the focus of these studies was to portray GIE in early stage primary tumors, whereas the changes induced by exposure to treatment and by the metastatic bottleneck have not been comprehensively addressed. However, a pan-cancer analysis of the prevalence and impact of diverse GIE events is currently lacking. Others have performed an extensive analysis of loss of heterozygosity (LOH) of HLA-I across thousands of tumor samples 10. ![]() Previous studies have performed cancer type-specific molecular profiling of GIE events and their phenotypic implications in several cancer types, including non-small-cell lung cancer 5, 6 (NSCLC) and colorectal carcinoma 7, among others 8, 9. Therefore, identification of GIE events across human cancers is key to understanding the interplay between cancer cells and the immune system, as well as to enable effective precision medicine based on immunotherapy. GIE alterations operate through different mechanisms, including partial or complete abrogation of neoepitope presentation 3 or suppression of proapoptotic signals from the surrounding immune cells 4. Escape from immune system recognition often involves tumor-specific genomic alterations in immune-related pathways, a process named genetic immune escape (GIE). Tumors acquire this capacity as a response to the accumulation of tumor-specific alterations, which may be presented-in the form of neoepitopes-by the major histocompatibility complex class I (MHC-I). 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.Ĭancer immune escape is the process whereby tumor cells prevent their elimination by the immune system 1, 2. 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. GIE prevalence is generally consistent between primary and metastatic tumors. One in four tumors harbors GIE alterations, with high mechanistic and frequency variability across cancer types. ![]() To address the complexity of the HLA-I locus in the germline and in tumors, we developed LILAC, an open-source integrative framework. We performed a pan-cancer characterization of GIE prevalence across six immune escape pathways in 6,319 uniformly processed tumor samples. However, whether late-stage metastatic tumors present differences in genetic immune escape (GIE) prevalence and dynamics remains unclear. Studies have characterized the immune escape landscape across primary tumors.
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