Exploiting the Innate Antitumor Activity of Human gammadelta-TCells for the Treatment of Prostate Cancer

摘要

We initially identified a CD2-mediated, interleukin (IL)-12 dependent signaling pathway which inhibits apoptosis in mitogen-stimulated human gamma/delta T-cells. We have since exploited this pathway to develop the methodologies allowing the large-scale ex vivo expansion of viable apoptosis- resistant - T cells. We have shown that apoptosis-resistant human T- cells retain significant innate, major histocompatibility complex (MHC)-unrestricted cytotoxicity against human prostate cancer cell lines. Purpose and scope: The aims of this project have been, (1) to characterize the extent and breadth of the antitumor cytotoxicity mediated by apoptosis resistant human GAMMA/DELTA -T cells against human prostate cancer cells ; (2) to define the general mechanisms involved in the recognition and lys is of sensitive prostate cancer cells by apoptosis -resistant GAMMA/DELTA -T cells ; and (3) to determine the extent to which apoptosis resistant GAMMA/DELTA- T cells can regulate the growth and metastasis of prostate cancer cells in vivo. Key findings: (1) Using the TRAMP transgenic mouse model of prostate cancer, we have formally demonstrated that absence of GAMMA/DELTA -T cells is permissive for the development of tumors. (2). Conversely, we have shown that adoptively transferred mouse GAMMA/DELTA -T cells are capable of moderating the growth of syngeneic mouse prostate cancer cells (cell line TRAMP C2) in vivo and that in treated mice, -T cells are shown to home to tumors in vivo. (3) - T cell numbers are reduced in the peripheral blood of patients with prostate cancer; though it is not yet clear if this is related to the development or progression of disease. (4) We have shown the in vivo capacity of human GAMMA/DELTA - T cells to kill human prostate cancer cells (PC -3) first xenografted into nude mice.