Provision of tumor‐specific CD4+ T cells to enhance tumor immunity in a murine model of prostate cancer

Abstract

T cell tolerance to tumor antigens is a considerable challenge to cancer immunotherapy. Our laboratory studies T cell tolerance to tumor antigens using 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 CD8+ (TcR‐I) cells into TRAMP mice resulted in rapid tolerization of the cells. The objective of the current study was to test the ability CD4+ TcR‐II cells to prevent or reverse TcR‐I cell tolerance. Naïve TcR‐II cells transferred into TRAMP mice proliferate in the lymph nodes, are transiently activated, and subsequently traffic to the prostate where they become tolerant by 10 days after transfer. We next tested whether the transient activation of TcR‐II cells was sufficient to prevent TcR‐I cell tolerization. Co‐transfer of naïve TcR‐II cells with TcR‐I cells initially enhanced the frequency, activation, survival and function of TcR‐I cells but this effect was not durable, as TcR‐I cells were eventually tolerized by 3 weeks after co‐transfer with TcR‐II cells. Furthermore, our preliminary data suggest that TcR‐II cells transferred 10 days after TcR‐I cells were unable to rescue TcR‐I cells from tolerization. Taken together, these data demonstrate that the powerful immunosuppressive environment of the developing TRAMP tumor can exert its effect on T cells, irrespective of provision of T cell help. On‐going studies will test whether conditioning TcR‐II cells affects their ability to prevent or reverse TcR‐I tolerance. 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.Supported in part by NCI IRP and DOD PCRP.