title: Radiotherapy-induced anti-tumor immunity contributes to the therapeutic efficacy of irradiation and can be augmented by CTLA-4 blockade in a mouse model.
abstract: OBJECTIVE
  There is growing evidence that tumor-specific immune responses play an important role in anti-cancer therapy, including radiotherapy. Using mouse tumor models we demonstrate that irradiation-induced anti-tumor immunity is essential for the therapeutic efficacy of irradiation and can be augmented by modulation of cytotoxic T lymphocyte (CTL) activity.
  
  
  METHODS
  C57BL/6 mice, syngeneic EL4 lymphoma cells, and Lewis lung carcinoma (LL/C) cells were used. Cells were injected into the right femurs of mice. Ten days after inoculation, tumors were treated with 30 Gy of local X-ray irradiation and their growth was subsequently measured. The effect of irradiation on tumor growth delay (TGD) was defined as the time (in days) for tumors to grow to 500 mm3 in the treated group minus that of the untreated group. Cytokine production and serum antibodies were measured by ELISA and flow cytometry.
  
  
  RESULTS
  In the EL4 tumor model, tumors were locally controlled by X-ray irradiation and re-introduced EL4 cells were completely rejected. Mouse EL4-specific systemic immunity was confirmed by splenocyte cytokine production and detection of tumor-specific IgG1 antibodies. In the LL/C tumor model, X-ray irradiation also significantly delayed tumor growth (TGD: 15.4 days) and prolonged median survival time (MST) to 59 days (versus 28 days in the non-irradiated group). CD8(+) cell depletion using an anti-CD8 antibody significantly decreased the therapeutic efficacy of irradiation (TGD, 8.7 days; MST, 49 days). Next, we examined whether T cell modulation affected the efficacy of radiotherapy. An anti-CTLA-4 antibody significantly increased the anti-tumor activity of radiotherapy (TGD was prolonged from 13.1 to 19.5 days), while anti-FR4 and anti-GITR antibodies did not affect efficacy.
  
  
  CONCLUSIONS
  Our results indicate that tumor-specific immune responses play an important role in the therapeutic efficacy of irradiation. Immunomodulation, including CTLA-4 blockade, may be a promising treatment in combination with radiotherapy.
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Yoshimoto
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Surgery, National University of Singapore, Singapore, Singapore; First Department of Surgery, University of Yamanashi, Yamanashi, Japan.
authors.forename: Kousaku
authors.initials: K
authors.lastname: Mimura
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Ando
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Oike
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Hiro
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Okonogi
authors.affiliation: First Department of Surgery, University of Yamanashi, Yamanashi, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Maruyama
authors.affiliation: First Department of Surgery, University of Yamanashi, Yamanashi, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Izawa
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Shin-ei
authors.initials: SE
authors.lastname: Noda
authors.affiliation: First Department of Surgery, University of Yamanashi, Yamanashi, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.affiliation: Department of Surgery, National University of Singapore, Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; First Department of Surgery, University of Yamanashi, Yamanashi, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kono
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakano
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology*; D018827:Carcinoma, Lewis Lung / Q000276:immunology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D007074:Immunoglobulin G / Q000276:immunology; D008223:Lymphoma / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011878:Radiotherapy / Q000379:methods; D011879:Radiotherapy Dosage; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D007074:Immunoglobulin G