MAP3K1 mutations confer tumor immune heterogeneity in hormone receptor–positive HER2-negative breast cancer

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Abstract

Treatment for hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) breast cancer, the most common type of breast cancer, has faced challenges such as endocrine therapy resistance and distant relapse. Immunotherapy has shown progress in treating triple-negative breast cancer, but immunological research on HR+/HER2– breast cancer is still in its early stages. Here, we performed a multi-omics analysis of a large cohort of patients with HR+/HER2– breast cancer (n = 351) and revealed that HR+/HER2– breast cancer possessed a highly heterogeneous tumor immune microenvironment. Notably, the immunological heterogeneity of HR+/HER2– breast cancer was related to mitogen-activated protein kinase kinase kinase 1 (MAP3K1) mutation and we validated experimentally that a MAP3K1 mutation could attenuate CD8+ T cell–mediated antitumor immunity. Mechanistically, MAP3K1 mutation suppressed MHC-I–mediated tumor antigen presentation through promoting the degradation of antigen peptide transporter 1/2 (TAP1/2) mRNA, thereby driving tumor immune escape. In preclinical models, the postbiotic tyramine could reverse the MAP3K1 mutation–induced MHC-I reduction, thereby augmenting the efficacy of immunotherapy. Collectively, our study identified the vital biomarker driving the immunological heterogeneity of HR+/HER2– breast cancer and elucidated the underlying molecular mechanisms, which provided the promise of tyramine as what we believe to be a novel therapeutic strategy to enhance the efficacy of immunotherapy.

Authors

Yu-Wen Cai, Cui-Cui Liu, Yan-Wu Zhang, Yi-Ming Liu, Lie Chen, Xin Xiong, Zhi-Ming Shao, Ke-Da Yu