Activating mutations in ESR1 contribute to an immunosuppressive breast tumor microenvironment by dampening cytokine secretion
Yu Gu, Dongmei Zuo, Qi-Xin Hu, Virginie Sanguin-Gendreau, Alain Pacis, Marie-Christine Guiot, Alexander Chih-Chieh Chang, Tarek Taifour, Chen Ling, Adrian V. Lee, Steffi Oesterreich, William J. Muller
Yu Gu, Dongmei Zuo, Qi-Xin Hu, Virginie Sanguin-Gendreau, Alain Pacis, Marie-Christine Guiot, Alexander Chih-Chieh Chang, Tarek Taifour, Chen Ling, Adrian V. Lee, Steffi Oesterreich, William J. Muller
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Research Article Immunology Oncology

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

Abstract

Patients with estrogen receptor+ (ER+, ESR1+) breast cancer are most at risk of relapse, where activating mutations in ESR1 promote metastasis and therapeutic resistance. These patients are also disadvantaged in responding to immunotherapies, the mechanisms of which remain to be elucidated. Here, we engineered a transgenic mouse model carrying either Y541S or D542G mutation in ESR1, mirroring the 2 most common mutations seen in patients. ESR1mut tumors do not differ in the total number of immune cells yet display downregulation in immune pathways and decreased immune-modulatory cytokines, including IL-17a and IL-1β. T cells and macrophages have lower IFN-γ and antigen presentation, respectively. Mechanistically, ESR1mut negatively regulates immune modulator expression and upregulates Stat5 to dampen cytokine expression. In concordance, validation on ESR1mut patient tumors shows decreased IL-17a and IL-1β. Collectively, our findings reveal that ESR1 mutations contribute to an immunosuppressive tumor microenvironment by dampening cytokine secretion and immune cell activity.

Authors

Yu Gu, Dongmei Zuo, Qi-Xin Hu, Virginie Sanguin-Gendreau, Alain Pacis, Marie-Christine Guiot, Alexander Chih-Chieh Chang, Tarek Taifour, Chen Ling, Adrian V. Lee, Steffi Oesterreich, William J. Muller

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Figure 2

Esr1 RNA abundance and ER activity validation in MIC WT and ESR1mut tumors.

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Esr1 RNA abundance and ER activity validation in MIC WT and ESR1mut tum...
(A) RNA fluorescence in situ hybridization (FISH) for mouse Esr1 and hematoxylin on endpoint mammary tumors of MIC WT, MIC ESR1-Y541Shomo, and MIC ESR1-D542Ghomo mice. (B) Example of image deconvolution and signal scoring scheme for RNA FISH of mouse Esr1 based on signal intensity. (C–E) Quantification of total Esr1 RNA FISH signal area, Esr1+ cells, and Esr1 H score, respectively. (F) Immunoblot for cyclin D1 and FOXA1 with their respective loading control (β-actin) on endpoint mammary tumor lysates of MIC WT, MIC ESR1-Y541Shomo, and MIC ESR1-D542Ghomo mice. (G and H) Quantification of immunoblot for cyclin D1 and FOXA1 normalized to their respective loading control, respectively. Scale bars: 100 μm (A), 50 μm (B). Arrows indicate positive Esr1 RNA-FISH signals. Mean ± SEM for data calculated using 1-way ANOVA with Tukey’s multiple-comparison test.