Microenvironment and Immunology Immunosuppressive and Prometastatic Functions of Myeloid-Derived Suppressive Cells Rely upon Education from Tumor-Associated B Cells

Myeloid-derived suppressive cells (MDSC) have been reported to promote metastasis, but the loss of cancer-induced B cells/B regulatory cells (tBreg) can block metastasis despite MDSC expan-sion in cancer. Here, using multiple murine tumor models and human MDSC, we show that MDSC populations that expand in cancer have only partially primed regulatory function and limited prometastatic activity unless they are fully educated by tBregs. Cancer-induced tBregs directly activate the regulatory function of both the monocyte and granulocyte subpopulations of MDSC, relying, in part, on TgfbR1/TgfbR2 signaling.MDSC fully educated in this manner exhibit an increased production of reactive oxygen species and NO and more efficiently suppress CD4þ and CD8þ T cells, thereby promoting tumor growth and metastasis. Thus, loss of tBregs or TgfbR deficiency in MDSC is sufficient to disable their suppressive function and to block metastasis. Overall, our data indicate that cancer-induced B cells/B regulatory cells are important regulatorsof the immunosuppressive andprometastatic functions of MDSC. Cancer Res; 75(17); 1–10. 2015 AACR