Emigration of tumor specific regulatory T cells from the bone marrow is triggered by S1P1 and correlates with their accumulation in breast tumors (TUM9P.1001)

High regulatory T cell (Treg) infiltration in breast tumors is associated with reduced survival. However, the source of tumor infiltrating Treg and signals underlying their migration from lymphoid organs to the tumor tissue remain elusive. We here demonstrate that pronounced Treg infiltration in human breast tumors correlates with a selective reduction of tumor antigen specifc Treg from the bone marrow. Using MHC-II tumor peptide tetramers we furthermore show that tumor specific bone marrow Treg selectively express Sphingosine-1-phosphate receptor 1 (S1P1), the receptor that mediates cell egress. S1P1 was upregulated in Treg upon TCR stimulation mediated by bone marrow resident antigen presenting cells and triggered selective Treg but not conventional T cell migration in response to S1P gradients between bone marrow and blood which we found to be significantly increased in breast cancer patients. Taken together, our data suggests a crucial role for bone marrow antigen presenting cells in regulating the surface expression of S1P1 on tumor specific Treg in the bone marrow which may represent an important source of tumor infiltrating Treg.