Peroxisome proliferator-activated receptor gamma (PPARgamma) 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-CSFR(int) immature monocytic fraction and a CD11b(hi+)Gr-1(hi)SSC(hi)Ly6G(hi)M-CSFR(neg) 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 gamma (PPARgamma) 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 PPARgamma ligands. Overall, our data identify PLA(2) and especially PPARgamma as new potential therapeutic targets to subvert macrophage-mediated CTL suppression in cancer.
Van Ginderachter
Jo A
JA
Laboratory of Cellular and Molecular Immunology, Department of Molecular and Cellular Interactions, Vlaams Interuniversitair Instituut voor Biotechnologie, Vrije Universiteit Brussel, Brussels, Belgium. jvangind@vub.ac.be
Meerschaut
Sofie
S
Liu
Yuanqing
Y
Brys
Lea
L
De Groeve
Kurt
K
Hassanzadeh Ghassabeh
Gholamreza
G
Raes
Geert
G
De Baetselier
Patrick
P
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D008024:Ligands; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D009000:Monocytes / Q000166:cytology; D009369:Neoplasms / Q000276:immunology*; D047495:PPAR gamma / Q000819:agonists / Q000502:physiology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000502:physiology; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology*; D019139:Tumor Escape / Q000276:immunology*
D008024:Ligands; D047495:PPAR gamma; D010741:Phospholipases A