P-selectin enhances growth and metastasis of mouse mammary tumors by promoting regulatory T cell infiltration into the tumors.

Abstract

P-selectin is an adhesion receptor that is mainly present on endothelial cells and platelets. We investigated the role of P-selectin in the regulation of different T cell subsets in the tumor microenvironment, and how that influences the growth and metastasis of mouse mammary cancer cell line 4T1 in Balb/c mice. The 4T1 cells (1×10(4) or 1×10(5)) were inoculated subcutaneously in the pre-shaved back skin of the P-selectin knockout (P-sel-/-) and wild-type (WT) mice. Mice were monitored twice weekly for the tumor growth measurements and survival studies. The tumors and the lungs were isolated for cytokine and T cell subset analyses at the end of the study. Mice lacking P-selectin had reduced tumor burden, higher survival and reduced metastasis compared to WT mice. Loss of P-selectin inhibited the infiltration of regulatory T cells and reduced pro-inflammatory cytokines, such as IL-4, IL-10, and TGFβ in the tumors. Furthermore, the CD8+ T cells and effector CD4+ T cells were functional and exhibited enhanced infiltration into the tumors of P-selectin knockout mice compared to WT mice. These results demonstrated that P-selectin is an important adhesion molecule vital for infiltration of regulatory T cells into the tumors. Thus, inhibiting P-selectin can have important therapeutic implications against breast cancer growth and metastasis.