Targeting MARCO can lead to enhanced dendritic cell motility and anti-melanoma activity.
We reported that murine tumor lysate-pulsed dendritic cells (TP-DC) could elicit tumor-specific CD4(+) and CD8(+) T cells in vitro and in vivo. In some limited cases, TP-DC treatments in vivo could also result in regression of established subcutaneous tumors and lung metastases. By gene array analysis, we reported a high level of expression of a novel member of the cell surface class A scavenger receptor family, MARCO, by murine TP-DC compared to unpulsed DC. MARCO is thought to play an important role in the immune response by mediating binding and phagocytosis, but also in the formation of lamellipodia-like structures and dendritic processes. We have now examined the biologic and therapeutic implications of MARCO expressed by TP-DC. In vitro exposure of TP-DC to a monoclonal anti-MARCO antibody resulted in a morphologic change of rounding with disappearance of dendritic-like processes. TP-DC remained viable after anti-MARCO antibody treatment; had little, if any, change in production of IL-10, IL-12p70 and TNF-alpha; but demonstrated enhanced migratory capacity in a microchemotaxis assay. The use of a selective inhibitor showed MARCO expression to be linked to the p38 mitogen-activated protein kinase (MAPK) pathway. In vivo, anti-MARCO antibody treated TP-DC showed better trafficking from the skin injection site to lymph node, enhanced generation of tumor-reactive IFN-gamma producing T cells, and improved therapeutic efficacy against B16 melanoma. These results, coupled with our finding that human monocyte-derived DC also express MARCO, could have important implications to human clinical DC vaccine trials.
Matsushita
Norimasa
N
Moffitt Comprehensive Cancer Center, SRB-3, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Komine
Hiroshi
H
Grolleau-Julius
Annabelle
A
Pilon-Thomas
Shari
S
Mulé
James J
JJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000378:metabolism; D019496:Cancer Vaccines; D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology; D048430:Cell Shape / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; C490460:MARCO protein, human; D047428:Protein Kinase Inhibitors; D011971:Receptors, Immunologic; D007371:Interferon-gamma