title: Targeting myeloid cells in the tumor microenvironment enhances vaccine efficacy in murine epithelial ovarian cancer.
abstract: Epithelial ovarian cancer (EOC) is typically diagnosed at advanced stages, and is associated with a high relapse rate. Patients in remission are ideal candidates for immunotherapy aimed at cure or prolonging disease-free periods. However, immunosuppressive pathways in the tumor microenvironment are obstacles to durable anti-tumor immunity. In a metastatic syngeneic mouse model of EOC, immunosuppressive macrophages and myeloid-derived suppressor cells (MDSCs) accumulate in the local tumor environment. In addition, resident peritoneal macrophages from non-tumor-bearing mice were highly immunosuppressive, abrogating stimulated T cell proliferation in a cell contact-dependent manner. Immunization with microparticles containing TLR9 and NOD-2 ligands (MIS416) significantly prolonged survival in tumor-bearing mice. The strategy of MIS416 immunization followed by anti-CD11b administration further delayed tumor progression, thereby establishing the proof of principle that myeloid depletion can enhance vaccine efficacy. In patients with advanced EOC, ascites analysis showed substantial heterogeneity in the relative proportions of myeloid subsets and their immunosuppressive properties. Together, these findings point to immunosuppressive myeloid cells in the EOC microenvironment as targets to enhance vaccination. Further studies of myeloid cell accumulation and functional phenotypes in the EOC microenvironment may identify patients who are likely to benefit from vaccination combined with approaches that deplete tumor-associated myeloid cells.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Anm Nazmul H
authors.initials: AN
authors.lastname: Khan
authors.affiliation: Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Nonna
authors.initials: N
authors.lastname: Kolomeyevskaya
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Singel
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Grimm
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Kirsten B
authors.initials: KB
authors.lastname: Moysich
authors.affiliation: Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Sayeema
authors.initials: S
authors.lastname: Daudi
authors.affiliation: Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Kassondra S
authors.initials: KS
authors.lastname: Grzankowski
authors.affiliation: Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Sashikant
authors.initials: S
authors.lastname: Lele
authors.affiliation: Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Ylagan
authors.affiliation: Innate Immunotherapeutics, Auckland, New Zealand.
authors.forename: Gill A
authors.initials: GA
authors.lastname: Webster
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Scott I
authors.initials: SI
authors.lastname: Abrams
authors.affiliation: Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Medicine, University at Buffalo School of Medicine, Buffalo, NY, USA.
authors.forename: Brahm H
authors.initials: BH
authors.lastname: Segal
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D001201:Ascites / Q000276:immunology; D039481:CD11b Antigen / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D018450:Disease Progression; D005260:Female; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology*; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D053473:Nod2 Signaling Adaptor Protein / Q000276:immunology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D051217:Toll-Like Receptor 9 / Q000276:immunology; D019139:Tumor Escape; D059016:Tumor Microenvironment; D014611:Vaccination
chemical_list: D000911:Antibodies, Monoclonal; D039481:CD11b Antigen; D019496:Cancer Vaccines; D008024:Ligands; C000605233:MIS416 vaccine; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D010047:Ovalbumin
keywords: macrophages; myeloid-derived suppressor cells; ovarian cancer; vaccination