Somatic Mutations and Neoepitope Homology in Melanomas Treated with CTLA-4 Blockade
Somatic Mutations and Neoepitope Homology in Melanomas Treated with CTLA-4 Blockade
Abstract Immune checkpoint inhibitors are promising treatments for patients with a variety of malignancies. Toward understanding the determinants of response to immune checkpoint inhibitors, it was previously demonstrated that somatic mutation burden is associated with benefit and a hypothesis was posited that neoantigen homology to pathogens may in part explain the link between somatic mutations and response. To further examine this hypothesis, we reanalyzed cancer exome data obtained from a previously published study of 64 melanoma patients treated with CTLA-4 blockade and a new dataset of RNA-Seq data from 24 of those patients. We found that the predictive accuracy does not increase as analysis narrows from somatic mutation burden to predicted MHC Class I neoantigens, expressed neoantigens, or homology to pathogens. Further, the association between somatic mutation burden and response is only found when examining samples obtained prior to treatment. Neoantigen and expressed neoantigen burden are also associated with response, but neither is more predictive than somatic mutation burden. Neither the previously-described tetrapeptide signature nor an updated method to evaluate neoepitope homology to pathogens were more predictive than mutation burden.
Ahuja Arun、Rubinsteyn Alexander、Hammerbacher Jeff、Hellmann Matthew D.、Miao Diana、Merghoub Taha、Aksoy Bulent Arman、Wolchok Jedd、Nathanson Tavi、Van Allen Eliezer、Snyder Alexandra
Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiGenetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiGenetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Medicine, Memorial Sloan Kettering Cancer Center and Department of Medicine, Weill Cornell Medical CollegeDepartment of Medical Oncology, Dana-Farber Cancer Institute, Broad Institute of MIT and Harvard, Center for Cancer Precision Medicine, Dana-Farber Cancer InstituteDepartment of Medicine, Memorial Sloan Kettering Cancer Center and Department of Medicine, Weill Cornell Medical College||Swim Across America¨CLudwig Collaborative Research Laboratory, Immunology Program, Ludwig Center for Cancer ImmunotherapyGenetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Medicine, Memorial Sloan Kettering Cancer Center and Department of Medicine, Weill Cornell Medical College||Swim Across America¨CLudwig Collaborative Research Laboratory, Immunology Program, Ludwig Center for Cancer ImmunotherapyGenetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Medical Oncology, Dana-Farber Cancer Institute, Broad Institute of MIT and Harvard, Center for Cancer Precision Medicine, Dana-Farber Cancer InstituteDepartment of Medicine, Memorial Sloan Kettering Cancer Center and Department of Medicine, Weill Cornell Medical College
肿瘤学医学研究方法基础医学
Ahuja Arun,Rubinsteyn Alexander,Hammerbacher Jeff,Hellmann Matthew D.,Miao Diana,Merghoub Taha,Aksoy Bulent Arman,Wolchok Jedd,Nathanson Tavi,Van Allen Eliezer,Snyder Alexandra.Somatic Mutations and Neoepitope Homology in Melanomas Treated with CTLA-4 Blockade[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/088286.点此复制
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