title: Two distinct mechanisms of augmented antitumor activity by modulation of immunostimulatory/inhibitory signals.
abstract: OBJECTIVE
  Blockade of CTL-associated antigen-4 (CTLA-4), an inhibitory immunomodulatory molecule on T cells, has been shown to enhance T-cell responses and induce tumor rejection, and a number of clinical trials with anti-CTLA-4 blocking monoclonal antibody (mAb) are under way. However, accumulating evidence indicates that anti-CTLA-4 mAb increases the number of CD4+CD25+Foxp3+ regulatory T cells (Treg) and that anti-CTLA4 mAb alone is often insufficient to reject established tumors in mice and humans. Thus, finding maneuvers to control Tregs and other immunosuppressive mechanisms remains a critical challenge.
  
  
  METHODS
  The potential to enhance antitumor immune responses by combining anti-CTLA-4 mAb with anti-glucocorticoid-induced tumor necrosis factor receptor family related gene (GITR) mAb, a costimulatory molecule that abrogates directly/indirectly Treg-mediated immune suppression or anti-CD25 mAb that depletes Tregs was analyzed with two tumor models, CT26 (a murine colon carcinoma cell line) and CMS5a (a murine fibrosarcoma cell line).
  
  
  RESULTS
  Anti-CTLA-4/anti-GITR mAb combination treatment exhibited far stronger antitumor effects compared with either antibody alone. This strong antitumor effect was attributed to (a) increased numbers of CD8+ T cells infiltrating tumor sites in anti-CTLA-4 mAb-treated mice and (b) increased cytokine secretion and Treg resistance of tumor-specific CD8+ T cells with strongly upregulated CD25 expression in anti-GITR mAb-treated mice, indicating distinct quantitative/qualitative changes induced by modulating CTLA-4 and GITR signaling.
  
  
  CONCLUSIONS
  This study shows that combined treatment with different immune modulators can augment antitumor immune responses and provides justification for exploring anti-CTLA-4/anti-GITR mAb combination treatment in the clinic.
authors.affiliation: Department of Cancer Vaccine, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Mitsui
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Daisuke
authors.initials: D
authors.lastname: Muraoka
authors.forename: Linan
authors.initials: L
authors.lastname: Wang
authors.forename: Takuro
authors.initials: T
authors.lastname: Noguchi
authors.forename: Eiichi
authors.initials: E
authors.lastname: Sato
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kondo
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: Takuma
authors.initials: T
authors.lastname: Kato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiku
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000276:immunology / Q000494:pharmacology; D056747:Immunomodulation / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007155:Immunologic Factors; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse