Tumoral immune suppression by macrophages expressing fibroblast activation protein-α and heme oxygenase-1.
The depletion of tumor stromal cells that are marked by their expression of the membrane protein fibroblast activation protein-α (FAP) overcomes immune suppression and allows an anticancer cell immune response to control tumor growth. In subcutaneous tumors established with immunogenic Lewis lung carcinoma cells expressing ovalbumin (LL2/OVA), the FAP(+) population is comprised of CD45(+) and CD45(-) cells. In the present study, we further characterize the tumoral FAP(+)/CD45(+) population as a minor subpopulation of F4/80(hi)/CCR2(+)/CD206(+) M2 macrophages. Using bone marrow chimeric mice in which the primate diphtheria toxin receptor is restricted either to the FAP(+)/CD45(+) or to the FAP(+)/CD45(-) subset, we demonstrate by conditionally depleting each subset that both independently contribute to the immune-suppressive tumor microenvironment. A basis for the function of the FAP(+)/CD45(+) subset is shown to be the immune inhibitory enzyme, heme oxygenase-1 (HO-1). The FAP(+)/CD45(+) cells are the major tumoral source of HO-1, and an inhibitor of HO-1, Sn mesoporphyrin, causes the same extent of immune-dependent arrest of LL2/OVA tumor growth as does the depletion of these cells. Because this observation of immune suppression by HO-1 expressed by the FAP(+)/CD45(+) stromal cell is replicated in a transplanted model of pancreatic ductal adenocarcinoma, we conclude that pharmacologically targeting this enzyme may improve cancer immunotherapy.
Authors' Affiliation: University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom.
James N
JN
Arnold
Lukasz
L
Magiera
Matthew
M
Kraman
Douglas T
DT
Fearon
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000276:immunology* / Q000628:therapy; D010450:Endopeptidases; D018093:Gelatinases / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007108:Immune Tolerance; D007167:Immunotherapy / Q000379:methods; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D012697:Serine Endopeptidases / Q000378:metabolism*; D000099167:Fibroblast Activation Protein Alpha
D010450:Endopeptidases; D018093:Gelatinases; D051547:Heme Oxygenase-1; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha