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

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

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.785526

DOI=10.3389/fimmu.2021.785526

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p><italic>MAP2K1/2</italic> genes are mutated in approximately 8% of melanoma patients; however, the impact of <italic>MAP2K1/2</italic> gene alterations on the efficiency of immunotherapy has not been clarified. This study focused on the correlation between <italic>MAP2K1/2</italic> gene mutations and the treatment response.</p></sec><sec><title>Methods</title><p>Six 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.</p></sec><sec><title>Results</title><p>Compared to patients with wild-type <italic>MAP2K1/2</italic>, those with <italic>MAP2K1/2</italic> 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 <italic>MAP2K1/2</italic> mutations and OS in the anti-PD-1-treated cohort. Subgroup Cox regression analysis suggested that patients with <italic>MAP2K1/2</italic> mutations received fewer benefits from anti-PD-1 monotherapy than from anti-CTLA-4 treatment. Furthermore, transcriptome profiling analysis revealed that melanoma tumours with <italic>MAP2K</italic> mutation was enriched in CD8<sup>+</sup> 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 <italic>MAP2K1/2</italic> mutations from anti-CTLA-4 treatment.</p></sec><sec><title>Conclusions</title><p><italic>MAP2K1/2</italic> 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 <italic>MAP2K1/2-</italic>mutated melanoma.</p></sec>