Association of PTPN11 mutation with tumor mutation burden and survival in melanoma patients treated with immune checkpoint inhibitors.

Abstract

e21596 Background: Melanoma is a serious skin cancer. Immune checkpoint inhibitors (ICIs) have shown durable responses and 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. Mutations of PTPN11 (Protein Tyrosine Phosphatase, Non-receptor type11) have been reported to be associated with higher response rate and prolonged survival in advanced Renal Cell Carcinoma, Glioblastoma. The association between PTPN11 mutation and the efficacy of ICIs for melanoma is unknown. Methods: Genomic and survival data of melanoma patients administrated with ICIs were retrieved from publicly accessible data (Melanoma.Allen2015.WES.110) and the association between PTPN11 mutation and progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and log-rank tests. At the same time，the association between PTPN11 mutation with TMB was also analyzed in this public immunotherapy-treated cohort(Melanoma.Allen2015.WES.110), Wilcoxon test was used for the comparison of TMB. In addition, Genomic, immune cell infiltration data of 466 patients with Skin Cutaneous Melanoma (SKCM) was obtained from The Cancer Genome Atlas (TCGA). The correlation analysis between immune cell infiltration and PTPN11 mutation status was further analyzed by CIBERSORT. Statistical significance was set at p = 0.05. Results: 3.6% (4/110) patients in the clinical cohort harbored PTPN11 mutation. Survival analysis in the public cohort demonstrated that PTPN11 mutation resulted in significantly longer OS (33.6 vs 8.5 months; HR, 0.16; p = 0.037) and an increasing trend on PFS without significantly difference (9.1 vs 2.8 months; HR, 0.3; P = 0.078) in melanoma patients treated with ICIs. Moreover, PTPN11 mutation is associated with higher TMB in public cohort (p = 0.01). Furthermore, the correlation analysis between immune infiltration and PTPN11 mutation status in melanoma shows that M1 macrophages increased significantly (p = 0.0014), CD8 T cells, plasma B cells and activated NK cells also show an upward trend (p = 0.17, p = 0.17 and p = 0.19) while the resting NK cells decreased significantly (p = 0.016)in melanoma patients with PTPN11 mutation. Conclusions: This study shows that PTPN11 mutation may serve as a potential positive biomarker of ICIs in melanoma since it relatively correlated with higher TMB. In addition, the up regulation of M1 macrophages and the down regulation of resting NK cells may be a potential mechanism for the better efficacy of ICIs in patients with PTPN11 mutation.