Scavenger receptor-A-targeted leukocyte depletion inhibits peritoneal ovarian tumor progression.
Immunosuppressive leukocytes are emerging as a critical factor in facilitating tumor progression. These leukocytes are converted by the tumor microenvironment to become tolerogenic, facilitate metastasis, and to aid in neovascularization. The predominant variety of suppressive leukocytes found in human and murine ovarian cancer are called vascular leukocytes (VLC), due to sharing functions and cell surface markers of both dendritic cells and endothelial cells. Using the ID8 murine model of ovarian cancer, the aim of this study was to test the efficacy of VLC elimination as an ovarian tumor therapy. We show that carrageenan-mediated depletion of peritoneal tumor-associated leukocytes inhibits ovarian tumor progression. We then identified scavenger receptor-A (SR-A) as a cell surface receptor that is robustly and specifically expressed within human and murine ovarian tumor ascites upon VLCs. Administration of anti-SR-A immunotoxin to mice challenged with peritoneal ID8 tumors eliminated tumor-associated VLCs and, importantly, substantially inhibited peritoneal tumor burden and ascites accumulation. Moreover, the toxin required targeting to SR-A because mice that received untargeted toxin did not exhibit inhibition of tumor progression. We conclude that SR-A constitutes a novel and specific target for efficacious immunotherapeutic treatment of peritoneal ovarian cancer.
Bak
S Peter
SP
Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
Walters
Julie Jo
JJ
Takeya
Motohiro
M
Conejo-Garcia
Jose R
JR
Berwin
Brent L
BL
D000818:Animals; D001201:Ascites / Q000473:pathology; D002351:Carrageenan / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000494:pharmacology; D007962:Leukocytes / Q000276:immunology* / Q000473:pathology; D051379:Mice; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D010534:Peritoneal Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051117:Scavenger Receptors, Class A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*
D000922:Immunotoxins; D051117:Scavenger Receptors, Class A; D002351:Carrageenan