Semaphorin7A and PD-L1 cooperatively drive immunosuppression during mammary involution and breast cancer

Postpartum mammary gland remodeling after a pregnancy/lactation cycle is characterized by mechanisms of immunosuppression. Here we show that SEMA7A promotes PD-L1 expression in immune cells of the mammary tissue during involution. These same phenotypes are mimicked in the microenvironment of SEMA7A-expressing tumors, which partially respond to PD-1/PD-L1 treatments in vivo. However, cells that remain after treatment are enriched for SEMA7A expression. Therefore, we tested a novel monoclonal antibody that directly targets SEMA7A-expressing tumors, in part, by reducing SEMA7A-mediated upregulation of PD-L1. In vivo, the SEMA7A monoclonal antibody also reduces tumor growth or promotes complete regression of mouse mammary tumors, reduces the immunosuppressive phenotypes in the tumor microenvironment and restores cytotoxic T cells suggesting that SEMA7A may be a candidate for a novel immune-based therapy for breast cancer patients.