Peroxisome proliferator-activated receptor γ (PPARγ) ligands reverse CTL suppression by alternatively activated (M2) macrophages in cancer

Abstract

Tumors may escape from immune control by the induction of CD11b +Gr-1- myeloid suppressor cells in the spleen. In this study, we demonstrate that this cell population can be subdivided into a CD11bhiGr-1intSSCloLy6GnegM- CSFRint immature monocytic fraction and a CD11bhi+Gr- 1hiSSChiLy6GhiM-CSFRneg granulocytic fraction. Upon in vitro culture, the monocytic CD11b+Gr-1 + cell fraction is sufficient for cytotoxic T lymphocyte (CTL) suppression, which is linked to the gradual differentiation of these monocytic cells into mature F4/80+ CD68+ macrophages. These CTL-suppressive macrophages are alternatively activated (M2), as demonstrated by the expression of known and novel M2 signature genes. In search of M2-associated genes involved in the suppressive activity, it is shown that stimulation of peroxisome proliferator-activated receptor γ (PPARγ) and inhibition of phospholipase A2 (PLA2) activity cooperate to alleviate CTL suppression. Of importance, purified tumor-associated macrophages display a similar M2 phenotype and are suppressive for antitumor CTLs, via a mechanism that can be almost completely reversed by PPARγ ligands. Overall, our data identify PLA2 and especially PPARγ as new potential therapeutic targets to subvert macrophage-mediated CTL suppression in cancer. © 2006 by The American Society of Hematology.