Abstract
Fatty acid transport protein 2 is required for the immunosuppressive activity of PMN-MDSCs.
Major finding: Fatty acid transport protein 2 is required for the immunosuppressive activity of PMN-MDSCs.
Concept: FATP2 mediates immunosuppression via uptake of arachidonic acid and synthesis of prostaglandin E2.
Impact: Inhibition of FATP2 may be a potential strategy to improve the efficiency of cancer therapy.
Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that contribute to failure of immunotherapy in cancer and are associated with poor clinical outcome. Despite similar origin and differentiation pathways, the mechanisms that drive distinct features of neutrophils and PMN-MDSCs remain poorly defined. Veglia and colleagues report that PMN-MDSCs upregulate fatty acid transport protein 2 (FATP2) to alter lipid metabolism and drive immunosuppressive function. PMN-MDSCs isolated from the spleens of tumor-bearing mice expressed higher levels of Slc27a2, the gene encoding FATP2. Total or conditional deletion of Scl27a2 from mice or PMNs, respectively, resulted in slower growth of transplantable mouse tumor models. Tumors established in mice reconstituted with bone marrow from Fatp2-knockout mice grew more slowly than in mice reconstituted with wild-type bone marrow, and depletion of CD8+ T cells from tumor-bearing mice restored tumor growth in Scl27a2-knockout mice. Fatp2 knockout from PMN-MDSCs resulted in decreased total and free arachidonic acid, reduced arachidonoyl-containing phospholipids, and lower intracellular and secreted levels of FATP2 metabolite prostaglandin E2 (PGE2). Treatment of PMNs with arachidonic acid favored expansion of PMN-MDSCs that expressed increased levels of PGE2 and suppressed antigen-specific T cell responses. Treatment of PMNs with GM-CSF resulted in increased phosphorylation of STAT5, which bound the Fatp2 promoter and upregulated its transcription. PMN-MDSCs from human patients with various cancers accumulated more lipids, expressed higher levels of FATP2, and contained significantly higher levels of free triglycerides, arachidonic acid, and PGE2 compared to healthy donors. Inhibition of FATP2 significantly delayed tumor growth in several tumor models, and combined inhibition of FATP2 with either anti-CTLA4 or anti-CSF1R antibodies resulted in potent anti-tumor effects. Taken together, these findings identify FATP2 as a critical regulator of the immunosuppressive functions of PMN-MDSCs and present a highly specific method for targeting PMN-MDSCs in cancer.
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