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

Abstract

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.