Osteopontin Shapes Immunosuppression in the Metastatic Niche

The matricellular protein osteopontin (OPN, Spp-1) is widely associated with cancer aggressiveness when produced by tumor cells, but its impac t. is uncertain when produced by leukocytes in the contex t. of the tumor stroma. In a broad study using Spp1(-/-) mice along with gene silencing in tumor cells, we obtained evidence of distinct and common activities of OPN when produced by tumor or host cells in a spontaneously metastatic model of breast cancer. Different cellular localization of OPN is associated with its distinct activities, being mainly secreted in tumor cells while intracellular in myeloid cells. OPN produced by tumor cells supported their survival in the blood stream, whereas both tumor-and host-derived OPN, particularly from myeloid cells, rendered the metastatic site more immunosuppressive. Myeloid-derived suppressor cells (MDSC) expanded with tumor progression at both primary and lung metastatic sites. Of the expanded monocytic and granulocytic cell populations of MDSCs, the rnonocytic subset was the predominant source of OPN. In Sppl(-/-)mice, the inhibition of lung metastases correlated with the expansion of granulocyte-oriented MDSCs. Notably, monocytic MDSCs in S'ppl mice were less suppressive than their wild-type counterparts clue to lower expression of arginase-1, IL6, and phospho-Statl Moreover, fewer regulatory T cells accumulated at the metastatic site in Sppl(-/-) mice. Our data find correlation with lung metastases of human mammary carcinomas that are associated with myeloid cells expressing OPN. Overall, our results unveiled novel functions for OPN in shaping local immunosuppression in the lung metastatic niche. 2014 AACR,