title: Cytoreduction surgery reduces systemic myeloid suppressor cell populations and restores intratumoral immunotherapy effectiveness.
abstract: BACKGROUND
  Multiple immunotherapy approaches have improved adaptive anti-tumor immune responses in patients with early stage disease; however, results have been less dramatic when treating patients with late stage disease. These blunted responses are likely due to a host of factors, including changes in the tumor microenvironment and systemic immunosuppressive features, which accompany advanced tumor states. We hypothesized that cytoreductive surgery could control these immunosuppressive networks and restore the potency of immunotherapy in advanced disease scenarios.
  
  
  METHODS
  To test these hypotheses, two representative intratumoral immunotherapies (an adenoviral vector encoding a suicide gene, AdV-tk, or a type-I interferon, Ad.IFNα) were tested in murine models of lung cancer. Cytoreductive surgery was performed following treatment of advanced tumors. Mechanistic underpinnings were investigated using flow cytometry, in vivo leukocyte depletion methods and in vivo tumor neutralization assays.
  
  
  RESULTS
  AdV-tk and Ad.IFNα were effective in treating early lung cancers, but had little anti-tumor effects in late stage cancers. Interestingly, in late stage scenarios, surgical cytoreduction unmasked the anti-tumor potency of both immunotherapeutic approaches. Immune mechanisms that explained restoration in anti-tumor immune responses included increased CD8 T-cell trafficking and reduced myeloid derived suppressor cell populations.
  
  
  CONCLUSIONS
  This study demonstrates that surgical resection combined with immunotherapy may be a rational therapeutic option for patients with advanced stage cancer.
authors: Department of Surgery, Thoracic Surgery Research Laboratory, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors: Jarrod D
authors: JD
authors: Predina
authors: Veena
authors: V
authors: Kapoor
authors: Brendan F
authors: BF
authors: Judy
authors: Guanjun
authors: G
authors: Cheng
authors: Zvi Gregory
authors: ZG
authors: Fridlender
authors: Steven M
authors: SM
authors: Albelda
authors: Sunil
authors: S
authors: Singhal
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D005434:Flow Cytometry; D015774:Ganciclovir / Q000627:therapeutic use; D005822:Genetic Vectors / Q000008:administration & dosage*; D007124:Immunoenzyme Techniques; D007167:Immunotherapy; D016898:Interferon-alpha / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000276:immunology / Q000601:surgery* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology* / Q000276:immunology; D013937:Thymidine Kinase / Q000235:genetics; D059016:Tumor Microenvironment
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D013937:Thymidine Kinase; D015774:Ganciclovir