The Predictive Value of MAP2K1/2 Mutations on Efficiency of Immunotherapy in Melanoma.

Ting Ye,Jie-Ying Zhang,Xin-Yi Liu,Jing Chen,Yao-Xu Chen,Si-Yue Yuan,Wen-Zhuan Xie,Meng-Mei Yang,Yu-Han Zhou,Cheng-Zhi Ye,Chan Gao,Meng-Li Huang

doi:10.3389/fimmu.2021.785526

Abstract

Background MAP2K1/2 genes are mutated in approximately 8% of melanoma patients; however, the impact of MAP2K1/2 gene alterations on the efficiency of immunotherapy has not been clarified. This study focused on the correlation between MAP2K1/2 gene mutations and the treatment response.MethodsSix metastatic melanoma clinical cohorts treated with immune checkpoint inhibitors [anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) or anti-programmed cell death-1 (PD-1)] were recruited in this study. RNA expression profiling results from each of these six cohorts and the Cancer Genome Atlas (TCGA) melanoma cohort were analysed to explore the mechanism related to immune activation.ResultsCompared to patients with wild-type MAP2K1/2, those with MAP2K1/2 mutations in an independent anti-CTLA-4-treated cohort had higher objective response rates, longer progression-free survival, and longer overall survival (OS). These findings were further validated in a pooled anti-CTLA-4-treated cohort in terms of the OS. However, there was no correlation between MAP2K1/2 mutations and OS in the anti-PD-1-treated cohort. Subgroup Cox regression analysis suggested that patients with MAP2K1/2 mutations received fewer benefits from anti-PD-1 monotherapy than from anti-CTLA-4 treatment. Furthermore, transcriptome profiling analysis revealed that melanoma tumours with MAP2K mutation was enriched in CD8+ T cells, B cells, and neutrophil cells, also expressed high levels of CD33 and IL10, implying a potential mechanism underlying the benefit of melanoma patients with MAP2K1/2 mutations from anti-CTLA-4 treatment.Conclusions MAP2K1/2 mutations were identified as an independent predictive factor for anti-CTLA-4 therapy in melanoma patients. Anti-CTLA-4 treatment might be more effective than anti-PD-1 therapy for patients with MAP2K1/2-mutated melanoma.

Highlights

MAP2K1/2 genes are mutated in approximately 8% of melanoma patients; the impact of MAP2K1/2 gene alterations on the efficiency of immunotherapy has not been clarified
Data analysis was performed using a cohort of 110 patients (Van Allen cohort) with metastatic melanoma treated with ipilimumab
Seven patients (6.36%) in this cohort harboured MAP2K1 or MAP2K2 mutations and had longer overall survival (OS) (49.2 months vs 8.3 months; hazard ratio (HR) = 0.2; 95% confidence interval (CI), 0.05–0.83; p = 0.0262; Figure 1A) and progression-free survival (PFS) (19.4 months vs 2.8 months; HR = 0.37; 95% confidence intervals (CI), 0.15–0.91; p = 0.0307; Figure 1B) than those with wild-type MAP2K1/2

Summary

Introduction

MAP2K1/2 genes are mutated in approximately 8% of melanoma patients; the impact of MAP2K1/2 gene alterations on the efficiency of immunotherapy has not been clarified. Ipilimumab, an anti-CTLA-4 monoclonal antibody, has been found to significantly improve overall survival (OS) and progression-free survival (PFS) and increase the long-term survival rate of patients with advanced melanoma [2, 3]. Second-generation ICIs targeting PD-1, namely nivolumab and pembrolizumab, have been reported to induce an increased response rate, OS, and PFS, with superior toxicity profiles [4, 5]. The identification of biomarkers to select patients who will be more responsive to ICIs is of utmost importance. Several genomic features, such as high mutational load, high neoantigen load, and tumour clonality have been found to be predictive of a favourable response to anti-CTLA-4 therapy in melanoma patients [7, 8]. Either high PD-L1 expression or high tumour mutational burden (TMB) has been recognized as predictors of the effectiveness of anti-PD-1 blockade in melanomas and other solid tumours [12, 13]

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