白鸟
(2025-03-31 14:35):
#paper：doi：doi.org/10.1038/s41588-024-01883-8, MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution Nat Genet(2024).
通过HLA分子呈递肿瘤新生抗原对于实现肿瘤免疫治疗至关重要。但肿瘤的免疫识别可能会因HLA分子被破坏而受到抑制。HLA被破坏的不同类型（突变、LOH、抑制和可变剪接）在癌症中很常见。
1.检测工具：作者开发了一个工具 MHC Hammer，检测MHC杂合性缺失（LOH） 、等位基因特异性突变及测量HLA表达和抑制。
2.肿瘤HLA变化：肺癌和乳腺癌队列中破坏性的HLA突变很少见，但HLA等位基因的LOH、抑制和肿瘤富集的可变剪接却很普遍。这突出了HLA转录组损坏的程度及其重要性，和HLA抑制和可变剪接在癌症进化中的作用。
3.HLA抑制与甲基化：HLA抑制和替代剪接事件的潜在机制可能是表观遗传。发现甲基化和HLA基因表达之间存在很强的关联。
4.展望：HLA替代剪接和抑制在多大程度上代表一种泛癌症免疫逃避机制需要更多的研究。
Nature Genetics,
2024-10.
DOI: 10.1038/s41588-024-01883-8
MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution
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Abstract:
AbstractDisruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% and 15% of LUAD, LUSC and ER+ cancers. Consistent with the importance of HLA dysfunction in tumor evolution, in LUADs, HLA LOH was associated with metastasis and LUAD primary tumor regions seeding a metastasis had a lower effective neoantigen burden than non-seeding regions. These data highlight the extent and importance of HLA transcriptomic disruption, including repression and alternative splicing in cancer evolution.
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