Exploiting the Innate Antitumor Activity of Human gammadelta-TCells for the Treatment of Prostate Cancer
Final rept. 1 Apr 2003-31 Mar 2006
ALABAMA UNIV IN BIRMINGHAM
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We initially identified a CD2-mediated, interleukin IL-12 dependent signaling pathway which inhibits apoptosis in mitogen-stimulated human gammadelta 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 GAMMADELTA -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 GAMMADELTA -T cells and 3 to determine the extent to which apoptosis resistant GAMMADELTA- 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 GAMMADELTA -T cells is permissive for the development of tumors. 2. Conversely, we have shown that adoptively transferred mouse GAMMADELTA -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 GAMMADELTA - T cells to kill human prostate cancer cells PC -3 first xenografted into nude mice.
- Anatomy and Physiology
- Medicine and Medical Research