title: Surgical Stress Abrogates Pre-Existing Protective T Cell Mediated Anti-Tumor Immunity Leading to Postoperative Cancer Recurrence.
abstract: Anti-tumor CD8+ T cells are a key determinant for overall survival in patients following surgical resection for solid malignancies. Using a mouse model of cancer vaccination (adenovirus expressing melanoma tumor-associated antigen (TAA)-dopachrome tautomerase (AdDCT) and resection resulting in major surgical stress (abdominal nephrectomy), we demonstrate that surgical stress results in a reduction in the number of CD8+ T cell that produce cytokines (IFNγ, TNFα, Granzyme B) in response to TAA. This effect is secondary to both reduced proliferation and impaired T cell function following antigen binding. In a prophylactic model, surgical stress completely abrogates tumor protection conferred by vaccination in the immediate postoperative period. In a clinically relevant surgical resection model, vaccinated mice undergoing a positive margin resection with surgical stress had decreased survival compared to mice with positive margin resection alone. Preoperative immunotherapy with IFNα significantly extends survival in surgically stressed mice. Importantly, myeloid derived suppressor cell (MDSC) population numbers and functional impairment of TAA-specific CD8+ T cell were altered in surgically stressed mice. Our observations suggest that cancer progression may result from surgery-induced suppression of tumor-specific CD8+ T cells. Preoperative immunotherapies aimed at targeting the prometastatic effects of cancer surgery will reduce recurrence and improve survival in cancer surgery patients.
authors.affiliation: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Abhirami A
authors.initials: AA
authors.lastname: Ananth
authors.affiliation: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Lee-Hwa
authors.initials: LH
authors.lastname: Tai
authors.affiliation: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Casey
authors.initials: C
authors.lastname: Lansdell
authors.affiliation: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.|Department of Medical Laboratory Technology, University of Tabuk, Tabuk, Saudi Arabia.
authors.forename: Almohanad A
authors.initials: AA
authors.lastname: Alkayyal
authors.affiliation: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Baxter
authors.affiliation: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Leonard
authors.initials: L
authors.lastname: Angka
authors.affiliation: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.|Department of Neurosurgery, The Second Hospital of Shandong University, Shandong, China.
authors.forename: Jiqing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Christiano
authors.initials: C
authors.lastname: Tanese de Souza
authors.affiliation: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Kyle B
authors.initials: KB
authors.lastname: Stephenson
authors.affiliation: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Kelley
authors.initials: K
authors.lastname: Parato
authors.affiliation: McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Bramson
authors.affiliation: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.affiliation: McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lichty
authors.affiliation: Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.|Department of Surgery, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Auer
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000276:immunology; D045744:Cell Line, Tumor; D007668:Kidney / Q000473:pathology / Q000601:surgery*; D008175:Lung Neoplasms / Q000276:immunology* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000276:immunology; D009374:Neoplasms, Experimental / Q000473:pathology / Q000601:surgery; D009392:Nephrectomy / Q000009:adverse effects; D013312:Stress, Physiological / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015815:Cell Adhesion Molecules; D009363:Neoplasm Proteins; C476587:Taa1 protein, mouse