Abstract A13: A combinatory treatment targeting CD25+ regulatory T cells and CTL-associated antigen-4 blockage enhanced anti-tumor immunity in the HLA-DR transgenic mouse model of prostate cancer
Authors: Klyushnenkova Elena N. , Alexander Richard B. 
Published: May 2013

Abstract
It is clearly established that the successful cancer immunotherapy will critically depend on the overcoming tolerance to “self” and negative immunoregulatory mechanisms. We have recently described a novel model of prostate cancer in double transgenic mice expressing human leukocyte antigen (HLA)-DR (HLA-DRB1*1501(DR2b)) and human prostate specific antigen (PSA) as a “self” antigen. In DR2bxPSA F1 mice, immunological tolerance to the transgenic mouse adenocarcinoma of prostate (TRAMP) tumor cells expressing PSA was established in a context of a “permissive” HLA-DR2b allele, and could be reversed by depleting CD25+ regulatory T cells (Tregs) prior to tumor inoculation. Several studies suggested that simultaneous targeting of both Tregs and negative regulatory pathway mediated by the T-cell inhibitory receptor CTL-associated antigen-4 (CTLA-4) may potentiate anti-tumor immune responses. We studied the effect of the combinatory treatment with anti-CD25 mAb and anti-CTLA-4 mAb on the growth of TRAMP-PSA tumor cells in DR2bxPSA F1 male mice. Single administration of anti-CD25 mAb (clone PC61) three days prior to tumor inoculation significantly increased PSA-specific CD8 T cell responses to the TRAMP-PSA tumor cells and delayed tumor growth compared to mice treated with isotype control antibodies. Similarly, treatment with anti-CTLA-4 mAb (clone 9D9) administered on days 3, 6 and 9 after tumor inoculation also significantly increased the levels CD8 T cells producing IFN-γ in response to the immunodominant H-2Db-restricted epitope PSA65–73 and delayed tumor growth. A combinatory treatment with both anti-CD25 and anti-CTLA-4 mAbs further enhanced anti-tumor immunity and caused a more profound delay in the tumor growth compared to each treatment alone. There were no tumor-free survivors among mice treated with anti-CD25 mAb alone (0 out of 21 mice), while 2 out of 21 mice treated with anti-CTLA-4 mAb alone (9.5%) and 3 out of 10 mice treated with a combination of anti-CD25 and anti-CTLA-4 mAbs (30%) survived tumor-free. Mice that survived a primary tumor challenge for 20 weeks demonstrated strong polyfunctional CD8 T cell memory responses to the secondary challenge with TRAMP-PSA tumors that was characterized by the significantly increased levels of PSA-specific IFN-γ+TNF-α+ CD8 T cells. Our data suggest that a combinatory treatment targeting Tregs and CTLA-4-mediated inhibitory pathways may be a promising approach for the prostate cancer immunotherapy.
Citation Format: Elena N. Klyushnenkova, Richard B. Alexander. A combinatory treatment targeting CD25+ regulatory T cells and CTL-associated antigen-4 blockage enhanced antitumor immunity in the HLA-DR transgenic mouse model of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A13.