Importance of PPARα in tumor-evoked Breg generation

Thursday, October 11, 2012 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center, Building 45	NIA	IMMUNO-13

Authors

• C Lee-Chang
• K Wejksza
• M Bodogai
• J Bonzo
• FJ Gonzalez
• A Martin-Montalvo Sanchez
• R de Cabo
• A Biragyn

Abstract

We recently reported that breast cancer cells induce the generation of a unique regulatory B-cell subset (tumor-evoked Bregs, tBregs) to promote cancer escape. tBregs suppress T-cell proliferation and induce conversion of FoxP3+ Tregs. We show that tBreg generation is promoted by metabolites of the 5-lipooxigenase (5-LO)/PPARα pathway produced by non-metastatic cancer cells. Metabolites like leukotriene (LT) B4 induce PPARα expression in B cells acting via BLT1/2 receptors. Genetic deficiency in PPARα abrogates the ability of B cells to become tBregs, suggesting the importance of this lipid metabolism-controlling factor in the differentiation of B cells. As strategy to inactivate this pathway we found that resveratrol, a natural polyphenol, efficiently blocks tBreg generation and reduce lung metastasis in mice with established breast cancer. B cells from RSV-treated mice could not suppress T cell proliferation and induce Treg conversion. Although activation of PPARα is essential for tBreg generation, its overexpression appears cytotoxic. Overall, cancer-produced 5-LO metabolites play important role in cancer escape and metastasis by directly inducing the generation of tBregs. As such, the 5LO/PPARα pathway needs to be controlled to combat cancer metastasis, a primary cause of a bad disease outcome. This work was entirely supported by the IRP of the NIH.

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