T cell tolerance to tumor antigens is a considerable challenge to cancer immunotherapy. To study T cell tolerance to tumor antigens, our laboratory utilizes the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model in combination with adoptive transfer of TcR transgenic T cells with specificity for a TRAMP tumor antigen. We previously reported that adoptive transfer of tumor-specific CD8+ (TcR-I) T cells into TRAMP mice resulted in their rapid tolerization. The objective of the current study was to test the ability CD4+ (TcR-II) T cells to enhance anti-tumor immunity by preventing TcR-I cell tolerance. CD4+ T cells play a central role in orchestrating the initial priming and the maintenance of immunity and have been shown to contribute to the development of effective anti-tumor immune responses. Naïve TcR-II adoptively transferred into TRAMP mice alone became activated in LN and trafficked to the prostate. Within the prostate, TcR-II cells initially functioned as T helper-1 (TH1) cells, as measured by their ability to secrete IL-2 or IFN-γ in response to their cognate tumor antigen, but became tolerant by 10 days after transfer. We next tested whether the transient activation of TcR-II T cells was sufficient to prevent the toleriazation of TcR-I T cells. Co-transfer of naïve TcR-II T cells with TcR-I T cells initially enhanced the expansion, activation, and function of TcR-I T cells. While a single co-transfer was insufficient to maintain TcR-I-mediated anti-tumor responsiveness, sustained provision of TcR-II help prevented tolerization of TcR-I cells and ultimately reduced tumor progression. These data demonstrate that tumor-specific CD4+ T cells are essential for the expansion, differentiation, and maintenance of anti-tumor CTL activity and can prevent the immunosuppressive tolerization of tumor-specific CTLs. In addition, delivery of tumor-specific CD4+ helper T cells also prevented the conversion of TcR-I cells into suppressor cells. Within TRAMP prostates, TcR-I cells acquired the capability to suppress the proliferation of naïve CD4+ and CD8+ T cells and exhibited a surface phenotype similar to regulatory T cells. This suppression was mediated at least inpart by secreted factors including TGF-&beta.; Taken together, these data demonstrate that the powerful immunosuppressive environment of the developing TRAMP tumor can exert its effect on T cells. By studying the ability of CD4+ T cells to enhance anti-tumor CTL activity, we hope to elucidate novel approaches to stimulate a more potent anti-tumor immune response. Maintaining T cell responses that favor anti-tumor immunity over the induction of tolerance or suppressor activity in the tumor microenvironment may have critical implications on the efficacy of cancer immunotherapies.
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