title: Perioperative influenza vaccination reduces postoperative metastatic disease by reversing surgery-induced dysfunction in natural killer cells.
abstract: OBJECTIVE
  Surgical removal of solid primary tumors is an essential component of cancer treatment. Surgery-induced dysfunction in natural killer (NK) cells has been linked to the development of metastases in animal models and patients with cancer. We investigated the activation of NK cells using influenza vaccine in the perioperative period to eradicate micrometastatic disease.
  
  
  METHODS
  Both the B16lacZ and 4T1 tumor models in immunocompetent mice were used to assess the in vivo efficacy of perioperative influenza vaccine administration. In healthy human donors and cancer surgery patients, we assessed NK cell function pre- and post-influenza vaccination using both in vivo and ex vivo assays.
  
  
  RESULTS
  Using the TLR3 agonist poly(I:C), we showed as proof-of-principle that perioperative administration of a nonspecific innate immune stimulant can inhibit surgery-induced dysfunction in NK cells and attenuate metastases. Next, we assessed a panel of prophylactic vaccines for NK cell activation and determined that inactivated influenza vaccine was the best candidate for perioperative administration. Perioperative influenza vaccine significantly reduced tumor metastases and improved NK cytotoxicity in preclinical tumor models. Significantly, IFNα is the main cytokine mediator for the therapeutic effect of influenza vaccination. In human studies, influenza vaccine significantly enhanced NK cell activity in healthy human donors and cancer surgery patients.
  
  
  CONCLUSIONS
  These results provide the preclinical rationale to pursue future clinical trials of perioperative NK cell activation, using vaccination in cancer surgery patients. Research into perioperative immune therapy is warranted to prevent immune dysfunction following surgery and eradicate metastatic disease.
authors.affiliation: Authors' Affiliations: Centre for Innovative Cancer Research, Ottawa Hospital Research Institute; Departments of Cellular and Molecular Medicine, Biochemistry, Microbiology, and Immunology, and Surgery, University of Ottawa, Ottawa, Canada; Department of Neurosurgery, The Second Hospital of Shandong University, Shandong, China; Targeted & Biological Therapies Group, Leeds Institute of Cancer Studies and Pathology, Leeds, United Kingdom; Department of Medical Laboratory Technology, University of Tabuk, Tabuk; and College of Applied Medical Sciences, Taibah University, Medina, Saudi Arabia.
authors.forename: Lee-Hwa
authors.initials: LH
authors.lastname: Tai
authors.forename: Jiqing
authors.initials: J
authors.lastname: Zhang
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Scott
authors.forename: Christiano Tanese
authors.initials: CT
authors.lastname: de Souza
authors.forename: Almohanad A
authors.initials: AA
authors.lastname: Alkayyal
authors.forename: Anu Abhirami
authors.initials: AA
authors.lastname: Ananth
authors.forename: Shalini
authors.initials: S
authors.lastname: Sahi
authors.forename: Robert A
authors.initials: RA
authors.lastname: Adair
authors.forename: Ahmad B
authors.initials: AB
authors.lastname: Mahmoud
authors.forename: Subash
authors.initials: S
authors.lastname: Sad
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Makrigiannis
authors.forename: Alan A
authors.initials: AA
authors.lastname: Melcher
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Auer
mesh_terms: D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D006801:Humans; D007252:Influenza Vaccines / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology* / Q000517:prevention & control* / Q000556:secondary / Q000601:surgery; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000601:surgery*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019990:Perioperative Care; D011184:Postoperative Period; D053633:Receptor, Interferon alpha-beta / Q000502:physiology; D013514:Surgical Procedures, Operative / Q000009:adverse effects*; D014407:Tumor Cells, Cultured; D014611:Vaccination
chemical_list: C508032:Ifnar1 protein, mouse; D007252:Influenza Vaccines; D053633:Receptor, Interferon alpha-beta