This work was supported by the Intramural Research Program, NIA/NIH.
The success of metastasis often depends on the ability of disseminating cancer cells to escape immune attack by utilizing the help of regulatory immune cells, a heterogeneous group of specialized cells of granulocytic, myeloid and lymphoid origins with seemingly redundant functions. Here, we discuss the importance of tumor-evoked Bregs (tBregs), a new subset of regulatory B cells 1,2. Cancer directly induces the generation of tBregs from resting B cells by producing lipid mediators, such as 5-lipoxygenase (5-LO) metabolites. 5-LO metabolites induce tBregs by targeting their PPARɑ3. Although tBregs can suppress effector T cell responses, we show that they facilitate metastasis by converting FoxP3+Treg cells 1,4 that block activity of effector NK cells and CD8+ T cells 1,2. In addition, as our modeling studies with ex vivo generated human myeloid cells and with tumor-bearing mice revealed, tBregs and cancer-associated B cells crosstalk with MDSCs. tBregs empower cancer-expanded MDSCs regulatory. Overall, our data underscore the importance of tBregs/cancer-associated B cells as key initiators of suppressive events needed for the success of cancer metastasis. The inactivation of tBregs or the blockage of any step of its immunoregulatory axis provides anti-metastatic benefits.