Abstract 5254: Association of USP6 mutation with tumor mutation burden and survival in melanoma patients treated with immune checkpoint inhibitors

Abstract

Abstract Background: Melanoma is a serious skin cancer. Immune checkpoint inhibitors (ICIs) including pembrolizumab, nivolumab, ipilimumab have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients and research exploring the association between gene mutation and clinical benefit is limited. USP6 (Ubiquitin-specific protease 6) mutation rate is high in melanoma. Studies have shown that USP6 functions as a tumor suppressor in Ewing Sarcoma through the activation of NK cells and macrophages, which indicates that USP6 activity may create a "hot" tumor microenvironment in immunotherapy. The association between USP6 mutation and survival in melanoma is unknown. Methods: The association between USP6 mutation with TMB and survival data was analyzed in melanoma patients from the public immunotherapy-treated cohort called Melanoma.Allen2015.WES.110, which worked as training cohort while another cohort called Melanoma.Hugo2016.WES.38 worked as validation cohort. Wilcoxon test was used for the comparison of TMB. OS (Overall survival) analysis were conducted in the public cohort using Kaplan-Meier curves and log-rank tests. In addition, the genomic and immune cell infiltration data of 466 patients with Skin Cutaneous Melanoma was obtained from TCGA and the correlation analysis was further analyzed by CIBERSORT. Statistical significance was set at p=0.05. Results: In the training cohort, 10.9% (12/110) melanoma patients harbored USP6 mutation. USP6 mutation is associated with higher TMB (p=0.0007) and results in significantly longer OS (21.3 vs 8.1 months; HR, 0.44; p=0.049).Meanwhile, the validation cohort shows that USP6 mutation results in higher TMB without significant difference (p=0.08) and significantly longer OS (31.5 vs 14.4 months; HR, 0.14; p=0.0026).Furthermore, the correlation analysis between immune infiltration and USP6 mutation status in melanoma shows that both M1 macrophages and follicular helper T cells increased significantly (p=0.02, p=0.033), while differential neutrophil decreased significantly (p=0.048). Conclusions: This study shows that USP6 mutation may serve as a potential positive biomarker of ICIs in melanoma since it correlated with higher TMB, the up regulation of M1 macrophages, follicular helper T cells and the down regulation of differential neutrophil. Citation Format: De Long, Dandan Fan, Yaoxu Chen, Mengli Huang. Association of USP6 mutation with tumor mutation burden and survival in melanoma patients treated with immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5254.