title: Antibody-Mediated Phosphatidylserine Blockade Enhances the Antitumor Responses to CTLA-4 and PD-1 Antibodies in Melanoma.
abstract: In tumor-bearing animals, the membrane phospholipid phosphatidylserine (PS) suppresses immune responses, suggesting that PS signaling could counteract the antitumor effect of antibody-driven immune checkpoint blockade. Here, we show that treating melanoma-bearing mice with a PS-targeting antibody enhances the antitumor activity of downstream checkpoint inhibition. Combining PS-targeting antibodies with CTLA-4 or PD-1 blockade resulted in significantly greater inhibition of tumor growth than did single-agent therapy. Moreover, combination therapy enhanced CD4(+) and CD8(+) tumor-infiltrating lymphocyte numbers; elevated the fraction of cells expressing the proinflammatory cytokines IL2, IFNγ, and TNFα; and increased the ratio of CD8 T cells to myeloid-derived suppressor cells and regulatory T cells in tumors. Similar changes in immune cell profiles were observed in splenocytes. Taken together, these data show that antibody-mediated PS blockade enhances the antitumor efficacy of immune checkpoint inhibition. Cancer Immunol Res; 4(6); 531-40. ©2016 AACR.
authors.affiliation: Department of Preclinical Research, Peregrine Pharmaceuticals, Inc., Tustin, California.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Freimark
authors.affiliation: Department of Preclinical Research, Peregrine Pharmaceuticals, Inc., Tustin, California.
authors.forename: Jian
authors.initials: J
authors.lastname: Gong
authors.affiliation: Hamon Center for Therapeutic Oncology Research, Departments of Surgery and Pharmacology, UT Southwestern Medical Center, Dallas, Texas.
authors.forename: Dan
authors.initials: D
authors.lastname: Ye
authors.affiliation: Department of Preclinical Research, Peregrine Pharmaceuticals, Inc., Tustin, California.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gray
authors.affiliation: Department of Preclinical Research, Peregrine Pharmaceuticals, Inc., Tustin, California.
authors.forename: Van
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Department of Preclinical Research, Peregrine Pharmaceuticals, Inc., Tustin, California.
authors.forename: Shen
authors.initials: S
authors.lastname: Yin
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, California.
authors.forename: Michaela M S
authors.initials: MM
authors.lastname: Hatch
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, California.
authors.forename: Christopher C W
authors.initials: CC
authors.lastname: Hughes
authors.affiliation: Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Schroit
authors.affiliation: Department of Preclinical Research, Peregrine Pharmaceuticals, Inc., Tustin, California.
authors.forename: Jeff T
authors.initials: JT
authors.lastname: Hutchins
authors.affiliation: Hamon Center for Therapeutic Oncology Research, Departments of Surgery and Pharmacology, UT Southwestern Medical Center, Dallas, Texas. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
authors.affiliation: Hamon Center for Therapeutic Oncology Research, Departments of Surgery and Pharmacology, UT Southwestern Medical Center, Dallas, Texas. xianming88@yahoo.com.
authors.forename: Xianming
authors.initials: X
authors.lastname: Huang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D016130:Immunophenotyping; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010718:Phosphatidylserines / Q000037:antagonists & inhibitors* / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D013154:Spleen / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D016207:Cytokines; C491383:Pdcd1 protein, mouse; D010718:Phosphatidylserines; D061026:Programmed Cell Death 1 Receptor