Sexual dimorphism and the effect of therapeutic low-dose estrogen in head and neck squamous cell carcinoma

Abstract

Abstract Differences between males and females have been identified in a variety of immune-related diseases. Generally, females show stronger immune responses, but also present a higher incidence of auto immune disease. Reasons for this have not been concretely identified but estrogen is believed to be a main driver of sex-dependent differences in biological behavior of disease and response to therapy. Using castration, oophorectomy, and estrogen rescue experiments in various preclinical head and neck squamous cell carcinoma (HNSCC) models, we identify estrogen as a regulator of immune response to treatment. The effect of estrogen is dose-dependent, as higher doses fail to demonstrate the beneficial effects of low dose estrogen. This response is dependent on regulatory T cells and dendritic cells, as knockout of these cell types eliminates the disparity between male and female responses. We also identified estrogen receptor beta agonists as a potential therapeutic strategy providing similar treatment benefit as low dose estrogen, reversing the effects of oophorectomy and stimulating cytotoxic T cell function. Survival analysis from HNSCC patients provided correlational validation of the potential benefit of estrogen as it demonstrates increased overall survival in younger women. Our data implicate low dose estrogen as a potential therapeutic strategy to enhance response to immunotherapy. Sana D. Karam is funded by the NIDCR (R01 DE028529-01, R01 DE028282-01) and Colorado Head and Neck Cancer SPORE and receives funding from Astra Zeneca, Genentech, and Ionis. This study was partly supported by the National Institutes of Health P30CA046934 Cancer Center Support Grant, including the Bioinformatics and Biostatistics Shared Resource Core, the Cancer Center Flow Cytometry Shared Resource, and the Genomics and Microarray Shared Resource at the University of Colorado. This study was also partly supported by the Cancer League of Colorado.