Activating mutations in ESR1 contribute to an immunosuppressive breast tumor microenvironment by dampening cytokine...

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Estrogen receptor-positive (ER+) breast cancer patients with ESR1 mutations face high relapse rates, metastasis, and therapeutic resistance.
• These patients often exhibit poor responses to immunotherapy, with underlying mechanisms requiring elucidation.

Purpose of the Study:

• To investigate the impact of common ESR1 mutations (Y541S, D542G) on the tumor microenvironment and immune response in ER+ breast cancer.
• To elucidate the mechanisms by which ESR1 mutations influence immune cell activity and cytokine expression.

Main Methods:

• Engineered transgenic mouse models with Y541S or D542G ESR1 mutations.
• Analyzed immune cell populations, immune pathways, and cytokine profiles (e.g., IL-17a, IL-1β, IFN-γ) in tumors.
• Validated findings in patient-derived ESR1-mutant tumors.

Main Results:

• ESR1-mutant tumors showed no difference in total immune cell count but exhibited downregulated immune pathways.
• Decreased immune-modulatory cytokines (IL-17a, IL-1β) and reduced T cell (IFN-γ) and macrophage (antigen presentation) activity were observed.
• ESR1 mutations were found to negatively regulate immune modulators and upregulate Stat5, leading to dampened cytokine expression.

Conclusions:

• ESR1 mutations promote an immunosuppressive tumor microenvironment in ER+ breast cancer.
• These mutations dampen crucial cytokine secretion and reduce immune cell activity, potentially explaining immunotherapy resistance.
• Findings were validated in patient tumors, highlighting the clinical relevance of ESR1 mutations in immune evasion.