Cancer-produced metabolites of 5-lipoxygenase induce tumor-evoked regulatory B Cells via peroxisome proliferator-activated receptor α

Breast cancer cells facilitate distant metastasis through the induction of immunosuppressive regulatory B cells, designated tBregs. We report in this study that, to do this, breast cancer cells produce metabolites of the 5-lipoxygenase pathway such as leukotriene B4 to activate the peroxisome proliferator- activated receptor a (PPARa) in B cells. Inactivation of leukotriene B4 signaling or genetic deficiency of PPARa in B cells blocks the generation of tBregs and thereby abrogates lung metastasis in mice with established breast cancer. Thus, in addition to eliciting fatty acid oxidation and metabolic signals, PPARa initiates programs required for differentiation of tBregs. We propose that PPARa in B cells and/or tumor 5-lipoxygenase pathways represents new targets for pharmacological control of tBreg-mediated cancer escape.