Tumoral immune suppression by macrophages expressing fibroblast activation protein-α and heme oxygenase-1.

Abstract

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: James N Arnold, Lukasz Magiera, Matthew Kraman, Douglas T Fearon
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 2 Issue 2 Pg. 121-6 (Feb 2014) ISSN: 2326-6074 [Electronic] United States
• PMID: 24778275 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Membrane Proteins
• Heme Oxygenase-1
• Endopeptidases
• Serine Endopeptidases
• fibroblast activation protein alpha
• Gelatinases

Topics

• Animals
• Carcinoma, Lewis Lung (immunology, therapy)
• Endopeptidases
• Gelatinases (metabolism)
• Heme Oxygenase-1 (metabolism)
• Immune Tolerance
• Immunotherapy (methods)
• Macrophages (immunology, metabolism)
• Membrane Proteins (metabolism)
• Mice, Inbred C57BL
• Mice, Transgenic
• Neoplasm Transplantation
• Serine Endopeptidases (metabolism)