title: Interleukin-12 Immunomodulation Delays the Onset of Lethal Peritoneal Disease of Ovarian Cancer.
abstract: The omental fat band (OFB) is the predominant site for metastatic seeding of ovarian cancer. Previously, we highlighted the influx and accumulation of neutrophils and macrophages in the OFB following syngeneic ovarian cancer cell seeding as an important factor in the development of a protumorigenic cascade. Here we investigated localized immunomodulation as a means of promoting a successful protective response. As an important TH1-type immunomodulator, interleukin (IL)-12 has previously been investigated clinically as an anticancer therapeutic. However, systemic IL-12 administration was associated with serious side effects, galvanizing the development of immune or accessory cells engineered to express secreted or membrane-bound IL-12 (mbIL-12). Using an mbIL-12-expressing cell variant, we demonstrate that localized IL-12 in the tumor microenvironment significantly delays disease development. The mbIL-12-mediated decrease in tumor burden was associated with a significant reduction in neutrophil and macrophage infiltration in the OFB, and correlated with a reduced expression of neutrophil and macrophage chemoattractants (CXCL1, -2, -3 and CCL2, -7). Vaccination with mitotically impaired tumor cells did not confer protection against subsequent tumor challenge, indicating that IL-12 did not impact the immunogenicity of the cancer cells. Our findings are in agreement with previous reports suggesting that IL-12 may hold promise when delivered in a targeted and sustained manner to the omental microenvironment. Furthermore, resident cells within the omental microenvironment may provide a reservoir that can be activated and mobilized to prevent metastatic seeding within the peritoneum and, therefore, may be targets for chemotherapeutics.
authors.affiliation: 1 Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University , Blacksburg, Virginia.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Cohen
authors.affiliation: 2 Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University , Blacksburg, Virginia.
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Shea
authors.affiliation: 1 Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University , Blacksburg, Virginia.
authors.forename: C Lynn
authors.initials: CL
authors.lastname: Heffron
authors.affiliation: 2 Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University , Blacksburg, Virginia.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Schmelz
authors.affiliation: 1 Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University , Blacksburg, Virginia.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Roberts
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D054410:Chemokine CCL7 / Q000235:genetics / Q000276:immunology; D054360:Chemokine CXCL1 / Q000235:genetics / Q000276:immunology; D054426:Chemokine CXCL2 / Q000235:genetics / Q000276:immunology; D019743:Chemokines, CXC / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D056747:Immunomodulation / Q000235:genetics*; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology*; D050152:Intra-Abdominal Fat / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D009852:Omentum / Q000276:immunology / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D010053:Ovary / Q000276:immunology / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000556:secondary; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*
chemical_list: C491768:Ccl2 protein, mouse; C515451:Ccl7 protein, mouse; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; C577095:Cxcl3 protein, mouse; D018664:Interleukin-12