CD8+ T cells respond to antigen stimulation through a process of activation, division, and differentiation to generate a large pool of activated effector cytolytic T lymphocytes (CTL). Many cancer patients harbor precursor CTL that can be activated to respond to many "self" tumor-associated epitopes. Vaccination with some of these epitopes can induce anti-tumor responses in some cases. However, various molecular and cellular mechanisms that tumors develop to successfully evade the host immune system have been identified. Some of these mechanisms target anti-tumor effector CTL that cannot be corrected by immunotherapy aimed only at activation of anti-tumor immune responses. Our preliminary data shows that effector memory phenotype bearing T cell becomes preferentially dysfunctional under conditions of exogenous oxidative stress but also undergo increased activation induced cell death (AICD) on antigenic encounter. Increased superoxide production can be seen in CTL undergoing AICD that can be rescued by pretreatment with superoxide dismutase mimetic MnTBAP. Based on our preliminary data we hypothesize that differential redox status between memory T cell subsets regulates the sensitivity towards AICD or apoptosis. Using MART-127-35 epitope specific human CTL and T cells from our novel transgenic h3T mouse that carries HLA-A2 restricted tyrosine specific functional TCR on both CD4+ and CD8+ T cells we propose to carry out the following: 1) To determine if differential redox state of the T cell subsets (TCM vs. TEM) regulates sensitivity to oxidative stress induced apoptosis and AICD by effecting intrinsic signaling molecules.;2) To determine extrinsic factors that differentially regulate oxidative stress mediated apoptosis and AICD of memory T cell subsets (TCM vs. TEM);and 3) To establish an in vivo model for evaluation of antioxidant treated T cells or antioxidant enzyme transduced T cells in tumor regression, persistence and memory. We believe that successful completion of the proposed work would help identify targets that could be used to improve survival of effector CTL and long-term memory development in patients receiving adoptive T cell therapy for cancer.
Despite T lymphocytes activated by cancer vaccination are virtually competent to attack and destroy neoplastic cells, the reason for their inefficacy in controlling tumor regression has been puzzling. Our data shows that it is both oxidative stress and antigen mediated preferential death of antigen-experienced/memory phenotype bearing CTL that might result in inadequate function. Since persistence of CTL is an important factor that affects the outcome of any immunotherapy protocol we believe that protecting effector lymphocytes by identifying and targeting the pathways to rescue CTL from premature death, their anti-tumor effect could be substantially improved.
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