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

J Clin Invest. 2024 Nov 12;135(2):e183656. doi: 10.1172/JCI183656.

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.

Keywords: Cancer; Immunology; Immunotherapy; Oncology.

MeSH terms

  • Animals
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / immunology
  • Breast Neoplasms* / pathology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Line, Tumor
  • Female
  • Humans
  • MAP Kinase Kinase Kinase 1* / genetics
  • MAP Kinase Kinase Kinase 1* / immunology
  • Mice
  • Mutation*
  • Neoplasm Proteins* / genetics
  • Neoplasm Proteins* / immunology
  • Receptor, ErbB-2* / genetics
  • Receptor, ErbB-2* / immunology
  • Receptor, ErbB-2* / metabolism
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism
  • Tumor Microenvironment* / genetics
  • Tumor Microenvironment* / immunology

Substances

  • Receptor, ErbB-2
  • ERBB2 protein, human
  • MAP3K1 protein, human
  • MAP Kinase Kinase Kinase 1
  • Neoplasm Proteins
  • Receptors, Estrogen
  • Receptors, Progesterone