A decreased T cell function can be demonstrated in approximately 50% of patients with cancer. The molecular basis for the diminished T cell response appears to be in part a decreased expression of signal transduction proteins in T cells, caused by mechanisms that remain unclear. Possible explanations have included the production of oxygen radicals by macrophages or the induction of apoptosis following the interaction of Fas ligand from the tumor cells with Fas-receptor in T cells. Alternatively, we proposed that """"""""chronic stimulation of T cells by antigen, in the absence of co-stimulatory signals, can lead to the decreased expression of T cell signal transduction proteins"""""""". Results obtained during the past grant period supported this hypothesis and revealed a new and as yet undescribed mechanism that can regulate T cell signal transduction and function in patients with cancer: The data demonstrates that L-arginine, a semi-essential amino-acid, regulates the expression of CD3zeta, Jak-3 and NF-kappaBp65, and thereby modifies T cell proliferation and the production of cytokines such as IFNgamma. Arginine levels are in turn closely controlled by arginase I, an enzyme produced by tumor cells and macrophages. The co-culture of T cells with arginase producing cells reproduces in vitro most of the changes previously described in patients making this an optimal model to study this complex phenomenon. Therefore the hypotheses for the next project period are: (A) arginase produced by tumor cells or macrophages in cancer patients, depletes arginine, which induces a decreased expression of certain T cell signal transduction molecules and results in a decreased T cell function. (B) This in turn can impair the anti-tumor effect of immunotherapy. To test these hypotheses we propose the following specific aims: ? ? 1 Test specific molecular mechanisms by which low concentrations of L-arginine regulate the expression and function of T cell signal transduction proteins and affect specific T cell functions.2.Test the prediction that arginase produced by tumor cells or macrophages regulates the availability of arginine and thereby alters T cell signal transduction.3.Test in tumor bearing mice the effects of arginase production on tumor growth, the response to immunotherapy and the potential use of arginase inhibitors as an adjuvant to immunotherapy.4.Test the prediction that arginase production in patients with cancer correlates with the presence of T cell signal transduction alterations.
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