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

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 CD11b(hi)Gr-1(int)SSC(lo)Ly6G(neg)M-CSFRint immature monocytic fraction and a CD11b(hi+)Gr-1(hi)SSC(hi)Ly6G(hi)M-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 (W), 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 gamma (PPAR gamma) and inhibition of phospholipase A(2) (PLA(2)) 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 PPAR gamma ligands. Overall, our data identify PLA2 and especially PPAR gamma as new potential therapeutic targets to subvert macrophage-mediated CTL suppression in cancer.