title: Surgical cytoreduction restores the antitumor efficacy of a Listeria monocytogenes vaccine in malignant pleural mesothelioma.
abstract: Recent studies suggest that immunotherapy may offer a promising treatment strategy for early-stage malignant pleural mesothelioma (MPM), but advanced tumor burden may limit the efficacy of immunotherapy. Therefore, we hypothesized that surgical cytoreduction could restore the efficacy of vaccine-based immunotherapy for MPM. We developed a murine model of MPM through transduction of a mesothelioma cell line with mesothelin. We used this model to evaluate the efficacy of a Listeria monocytogenes vaccine expressing mesothelin. Tumor growth was significantly inhibited at four weeks in animals vaccinated two weeks prior to tumor cell inoculation as compared to those given an empty vector control (1371 ± 420 mm(3) versus 405 ± 139 mm(3); p < 0.01). Mice vaccinated one week prior to tumor challenge also displayed significant reduction in tumor volume (1227 ± 406 mm(3) versus 309 ± 173 mm(3); p < 0.01). The vaccine had no effect when administered concurrently with tumor challenge, or after tumors were established. Flow cytometry showed reduced mesothelin expression in large tumors, as well as tumor-associated immunosuppression due to increased myeloid derived suppressor cells (MDSCs). These factors may have limited vaccine efficacy for advanced disease. Surgical cytoreduction of established tumors restored the antitumor potency of the therapeutic vaccine, with significantly reduced tumor burden at post-operative day 18 (397 ± 103 mm(3) versus 1047 ± 258 mm(3); p < 0.01). We found that surgery reduced MDSCs to levels comparable to those in tumor-naïve mice. This study demonstrates that cytoreduction surgery restores the efficacy of cancer vaccines for MPM by reducing tumor-related immunosuppression that impairs immunotherapy.
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, 6 White 3400 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Kennedy
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, 6 White 3400 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Brendan F
authors.initials: BF
authors.lastname: Judy
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, 6 White 3400 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Pratik
authors.initials: P
authors.lastname: Bhojnagarwala
authors.affiliation: Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Moon
authors.affiliation: Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Zvi G
authors.initials: ZG
authors.lastname: Fridlender
authors.affiliation: Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, 6 White 3400 Spruce Street, Philadelphia, PA 19104, USA. Electronic address: Sunil.Singhal@uphs.upenn.edu.
authors.forename: Sunil
authors.initials: S
authors.lastname: Singhal
mesh_terms: D000818:Animals; D001428:Bacterial Vaccines / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D065426:Cytoreduction Surgical Procedures; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology*; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology* / Q000601:surgery*; D008212:Lymphocyte Depletion; D000090204:Mesothelin; D008654:Mesothelioma / Q000276:immunology* / Q000601:surgery*; D000086002:Mesothelioma, Malignant; D051379:Mice; D008810:Mice, Inbred C57BL; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D001428:Bacterial Vaccines; D019496:Cancer Vaccines; D058851:GPI-Linked Proteins; C000715528:Msln protein, mouse; D000090204:Mesothelin
keywords: Malignant mesothelioma; Surgical cytoreduction; Vaccine immunotherapy