封锁
免疫检查点
免疫系统
癌症免疫疗法
免疫疗法
免疫学
医学
渗透(HVAC)
癌症研究
生物
受体
内科学
物理
热力学
作者
Han Zhang,Sanghoon Lee,Renee R. Muthakana,Binfeng Lu,David N. Boone,D.H. Lee,Xiao-Song Wang
出处
期刊:Cancer immunology research
[American Association for Cancer Research]
日期:2024-02-09
卷期号:: OF1-OF9
标识
DOI:10.1158/2326-6066.cir-22-0637
摘要
Abstract Immune checkpoint blockade (ICB) can induce durable cancer remission. However, only a small subset of patients gains benefits. While tumor mutation burden (TMB) differentiates responders from nonresponders in some cases, it is a weak predictor in tumor types with low mutation rates. Thus, there is an unmet need to discover a new class of genetic aberrations that predict ICB responses in these tumor types. Here, we report analyses of pan-cancer whole genomes which revealed that intragenic rearrangement (IGR) burden is significantly associated with immune infiltration in breast, ovarian, esophageal, and endometrial cancers, particularly with increased M1 macrophage and CD8+ T-cell signatures. Multivariate regression against spatially counted tumor-infiltrating lymphocytes in breast, endometrial, and ovarian cancers suggested that IGR burden is a more influential covariate than other genetic aberrations in these cancers. In the MEDI4736 trial evaluating durvalumab in esophageal adenocarcinoma, IGR burden correlated with patient benefits. In the IMVigor210 trial evaluating atezolizumab in urothelial carcinoma, IGR burden increased with platinum exposure and predicted patient benefit among TMB-low, platinum-exposed tumors. Altogether, we have demonstrated that IGR burden correlates with T-cell inflammation and predicts ICB benefit in TMB-low, IGR-dominant tumors, and in platinum-exposed tumors.
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