Estrogen signaling through estrogen receptor beta in Tregs regulates the differential response to therapy in head and neck squamous cell carcinoma 2310155

Abstract Introduction Immunotherapies (IO) have largely failed in head and neck squamous cell carcinoma (HNSCC). The subset of patients who respond to therapy tend to be premenopausal women. Estrogen (E2)-based hormone replacement therapy (HRT) has been shown to impart a survival advantage in HNSCC with 22% lower risk for ever-users of HRT, supporting the role of sex hormones as a driver of this advantage. It has been shown that estrogen receptors influence the immunosuppressive activity of regulatory T cells (Tregs), which are known drivers of resistance to IO in HNSCC. Based on these previous findings, we hypothesized that E2 reduces the immunosuppressive functionality of Tregs in the HNSCC tumor microenvironment (TME), thus enhancing effector T cell function. Methods We utilized the MOC2 and LY2 orthotopic models of HNSCC, implanted into C57BL/6 and BALB/C mice, respectively. Using surgical, pharmacologic, and genetic methods, we manipulated the level of sex hormones present to study their role in tumor growth, their impact on the TME using flow cytometry, and their effect on Treg cell state in vitro using qRT-PCR. Results We demonstrate that supplemented E2 leads to immune cell differences within the TME that are associated with improved response to radioimmunotherapy. We show that treatment with an estrogen receptor beta (ERβ) agonist results in a reduction of Treg immunosuppression and an increase in effector T cell functionality, leading to decreased tumor growth. Concordant with these findings, we found that conditional deletion of ERβ in male Tregs blocks the decrease in tumor growth observed with E2 supplementation. We provide further evidence that E2 signaling through ERβ in Tregs is decreasing their suppressive state via a decrease in stability. Conclusion This study reveals ERβ signaling in Tregs as a mediator of the immune response in HNSCC. Our findings provide rationale for therapeutic integration of E2 or ERβ agonists in immunotherapy clinical trials for males and post-menopausal females with HNSCC. Funding Source T32-AI007405, R01 DE028529-01, R01 DE028282-01, R01 CA284651-01 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)