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

Yuwen Cai,¹ Cui-cui Liu,¹ Yanwu Zhang,² Yiming Liu,¹ Lie Chen,¹ Xin Xiong,¹ Zhiming Shao,¹ and Ke-Da Yu¹

Published November 12, 2024 - More info

Hormone receptor-positive (HR⁺)/human epidermal growth factor receptor 2-negative (HER2⁻) breast cancer, the most common type of breast cancer, is facing 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 HR⁺/HER2^- breast cancer patients (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 MAP3K1 mutation and we validated experimentally that 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) mRNAs, thereby driving tumor immune escape. In preclinical models, the postbiotics 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 a novel therapeutic strategy to enhance the efficacy of immunotherapy.

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

Yuwen Cai,¹ Cui-cui Liu,¹ Yanwu Zhang,² Yiming Liu,¹ Lie Chen,¹ Xin Xiong,¹ Zhiming Shao,¹ and Ke-Da Yu¹

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

Yuwen Cai,1 Cui-cui Liu,1 Yanwu Zhang,2 Yiming Liu,1 Lie Chen,1 Xin Xiong,1 Zhiming Shao,1 and Ke-Da Yu1

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Yuwen Cai,¹ Cui-cui Liu,¹ Yanwu Zhang,² Yiming Liu,¹ Lie Chen,¹ Xin Xiong,¹ Zhiming Shao,¹ and Ke-Da Yu¹