Abstract 5318: CD4+CD25+ regulatory T cells are involved in the downregulation of antitumor CD8 T-cell response and tumor progression in HLA-DR2b transgenic mouse model of prostate cancer
Authors: Klyushnenkova Elena N. , Kouiavskaia Diana V. , Sausville Justin , Alexander Richard B. 
Published: February 2011

We have recently described a novel mouse model of prostate cancer in transgenic mice engineered to express Human Leukocyte Antigen (HLA)-DRB1*1501 (DR2b in old nomenclature) (J. Immunol. 2009, 182:1242-1246). Using these mice, we investigated the impact of HLA-DR2b on the growth of prostate-specific antigen (PSA)-expressing Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) tumor cells. We demonstrated that a “permissive” HLA class II allele could change the pattern of anti-tumor immune response resulting in failure of tumor rejection. The simple presence of HLA-DR2b was all that was required in our model for the development of strong humoral immune responses to the tumor antigen (PSA), suppression of CD8 T cell responses and enhanced growth of the tumor. In contrast, mice bearing class II allele that did not support CD4 T cell response to PSA (I-Ab), developed strong CD8 T cell response in the absence of antibody response, and rejected PSA-expressing tumors. One of the major mechanisms by which the presence of CD4 T cell epitope in PSA can negatively affect anti-tumor immunity may include CD4+CD25+ regulatory T cells (Treg) that can be selectively activated in an antigen-specific manner in DR2b+ mice. We found that the depletion of CD4+CD25+ Treg cells prior to tumor inoculation resulted in the significant enhancement of PSA-specific CD8 T cell response in DR2b+ mice. Moreover, we also found that depletion of CD25+ T cells prior to tumor inoculation significantly delayed TRAMP-PSA tumor growth (p=0.01, log rank test). These results indicated that low level of CD8 T cell-mediated IFN-γ response against TRAMP-PSA tumors in DR2b+ mice is an active process of immune suppression mediated by CD4+CD25+ Treg cells, and that the activation of Treg cells can be involved in tumor progression in our model. We also analyzed a composition of the tumor-infiltrating leukocytes (TIL) in DR2b+ and DR2b- mice bearing TRAMP-PSA tumors by flow cytometry. The analysis of infiltrating CD3+ T cells revealed significant strain-specific differences. In DR2b+ mice, CD4+ T cell were accumulated in larger number compared to DR2b- mice, and a significant proportion of CD4+ cells expressed CD25. These cells were also foxp3+. These observations are consistent with other data in our model, and confirm that 1) HLA-DR2b-dependent Treg cell activation may be involved in tumor progression in DR2b+ mice, and 2) lack of such activation in DR2b- mice can result in the efficient CD8 T cell response and tumor rejection.

Supported by a grant from the US Department of Veterans Affairs and a pilot grant from the Baltimore Research and Education Foundation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5318.