title: Breaking immune tolerance by targeting CD25+ regulatory T cells is essential for the anti-tumor effect of the CTLA-4 blockade in an HLA-DR transgenic mouse model of prostate cancer.
abstract: BACKGROUND
  Recent studies suggest that the cancer immunotherapy based on the blockade of the CTLA-4-mediated inhibitory pathway is efficacious only in select populations, predominantly for immunogenic tumors or when delivered in combination with modalities that can break immunologic tolerance to tumor antigens.
  
  
  METHODS
  We studied the effect of CD25+ cell depletion and CTLA-4 blockade on the growth of Transgenic Mouse Adenocarcinoma of Prostate (TRAMP)-PSA tumor cells in DR2bxPSA F1 mice. In these mice, immunological tolerance to PSA was established in a context of the HLA-DRB1*1501(DR2b) allele.
  
  
  RESULTS
  In our model, single administration of anti-CD25 antibody prior to tumor inoculation significantly increased IFN-γ production in response to the CD8 T cell epitope PSA65-73 , and delayed TRAMP-PSA tumor growth compared to mice treated with isotype control antibodies. In contrast, the anti-tumor effect of the anti-CTLA-4 antibody as a monotherapy was marginal. The combinatory treatment with anti-CD25/anti-CTLA-4 antibodies significantly enhanced anti-tumor immunity and caused more profound delay in tumor growth compared to each treatment alone. The proportion of tumor-free animals was higher in the group that received combination treatment (21%) compared to other groups (2-7%). The enhanced anti-tumor immunity in response to the CD25 depletion or CTLA-4 blockade was only seen in the immunogenic TRAMP-PSA tumor model, whereas the effect was completely absent in mice bearing poorly immunogenic TRAMP-C1 tumors.
  
  
  CONCLUSIONS
  Our data suggest that breaking immunological tolerance to "self" antigens is essential for the therapeutic effect of CTLA-4 blockade. Such combinatory treatment may be a promising approach for prostate cancer immunotherapy.
authors.affiliation: Department of Surgery, Division of Urology, University of Maryland, Baltimore, Maryland; VA Maryland Health Care System, Baltimore, Maryland.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Klyushnenkova
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Riabov
authors.forename: Diana V
authors.initials: DV
authors.lastname: Kouiavskaia
authors.forename: Ashley
authors.initials: A
authors.lastname: Wietsma
authors.forename: Min
authors.initials: M
authors.lastname: Zhan
authors.forename: Richard B
authors.initials: RB
authors.lastname: Alexander
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D004195:Disease Models, Animal; D015802:HLA-DR2 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017430:Prostate-Specific Antigen / Q000097:blood / Q000276:immunology; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000628:therapy*; D011897:Random Allocation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D015802:HLA-DR2 Antigen; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D017430:Prostate-Specific Antigen
keywords: CTL-associated antigen-4; HLA-DR2 transgenic mice; TRAMP tumor; prostate-specific antigen; regulatory T cells