LIPOXINS SELECTIVELY CHANGE M2‐LIKE PHENOTYPE OF TUMORASSOCIATED MACROPHAGES BY CHANGING THEIR UNIQUE METABOLIC PROFILE AND IMPAIRING TUMOR PROGRESSION

Abstract

In tumor microenvironments, most tumor‐associated macrophages (TAM) exhibit a characteristic M2 phenotype that favors tumor development, with deficient production of NO and ROS, key features of pro‐inflammatory M1 cytotoxic macrophages. Evidences have shown a positive correlation between high TAM density and poor prognosis. The balance between the different tumor derived mediators may modulate the outcome of the Mϕ response and consequent tumor development. Lipoxins (LX) are specialized pro‐resolving lipid mediators, able to shift inflammatory monocytes and macrophages towards M2‐like profile, but their effects on TAMs remained non‐elucidated. We have shown that, in vitro, LX selectively induce a switch of TAM M2‐like phenotype towards an M1‐like profile, increasing ROS and NO production, and enabling these cells to promote tumor cell apoptosis. LX did not affected the M2 profile of IL‐4‐stimulated macrophages. In vivo, the treatment of tumor‐bearing mice with LX, diminished the population of LY6Chi monocytes (TAM precursors) in spleen, blood and bone marrow, decreasing macrophage infiltration into the tumor, reducing the M2 markers expression on TAMs, and impairing tumor progression, increasing mice survival. The differential activation of macrophages is supported by profound intracellular metabolic changes, being well accepted that the pro‐inflammatory M1/M(LPS+IFN‐γ) phenotype rely on aerobic glycolysis, while anti‐inflammatory M2/M(IL‐4) macrophages depend on oxidative metabolism. However, little is known about TAM metabolism. We investigated the metabolic profile and requirements of TAMs, analyzing the lipoxin effects on their metabolic pathways. We show for the first time that despite TAMs present high expression of M2 markers, similarly to the M1, but distinct from M2 cells, have high glycolytic activity, with high lactate secretion, mTOR/Akt activity and increased GLUT‐1 expression. Inhibition of glycolysis, but not the oxidative phosphorylation or PPP, decreased M2 markers expression in TAMs. The inhibition of PPP impairs lipoxin to shift the M2‐profile and restore cytotoxic properties in TAMs. In conclusion, TAMs although phenotyped as M2, are metabolically distinct from these cells, being rather similar to M1, depending on the glycolytic metabolism to support their profile and functions, that lipoxin effects rely on PPP activation.Support or Funding Informationby: FAPERJ # E‐26/202.782/2017; CAPES: Finantial code # 001; CAPES/PROEX # 0574/2018; CNPq # 302413/2017‐0; 118566/2017‐2, Brazil.