Sex-Specific Immune Responses and Immunomodulatory Pathways in Breast Cancer

Abstract

Breast cancer is a disease that affects women and men. Although less prevalent, male patients have worse disease outcomes than female patients. Sex describes characteristic biological factors associated with females and males. Sex biases are evident in the development and pathologic responses of the immune system. However, male breast cancer is managed based on our knowledge of the female disease and thus the immunobiology of male breast cancer is hugely understudied. These studies explore the role of sex and sex-related factors in shaping the immune microenvironment in breast cancer by utilizing the MMTV-PyMT transgenic murine model of estrogen receptor-positive (ER+) breast cancer. Our findings reveal distinct differences in immune cell composition, subtype frequencies, and signaling pathways between female and male tumor-bearing mice, suggesting sex-specific immune profiles that may influence disease pathology. Additionally, we demonstrate that tumor hormone receptor (HR) status is associated with the overall immune landscape of implanted tumors. However, estrogen-driven macrophage responses are more pronounced in female tumor-bearing mice, regardless of tumor HR expression. Preliminary studies also identified the receptor for advanced glycation end products (RAGE) as a potential modulator of immune responses, showing differential effects between sexes. These results underscore the importance of considering sex in breast cancer immunity and highlight a regulator of tumor immunity in a sex-dependent manner. Future research will be necessary to validate these findings and explore their clinical relevance.