Increasing Thiols for Improving T cell Immunotherapy

ABSTRACT New strategies to improve adoptive cell therapy (ACT) protocols are emerging to enhance in vivo persistence of adoptively transferred tumor epitope-specific T cells and overcome tumor-induced immunosuppression. Our preliminary data suggests that there is a direct correlation between the long-lived central memory T cells (Tcm) and their anti-oxidant capacity. Overexpression of thioredoxin-1 (Trx), a critical molecule that regulates cell- surface thiols (c-SH), increased Tcm phenotype in T cells obtained from TCR transgenic mouse crossbred with Trx transgenic mouse, or engineering human T cells with a retroviral vector with TCR and Trx together. These preliminary observations led us to hypothesize that “the presence of Trx drives tumor-reactive T cells to a c-SHhi phenotype, which results in increased persistence in the oxidative tumor microenvironment and improved tumor control.andquot; We propose to further strengthen the translational aspect of this strategy by determining if strategies to increase anti-oxidant capacity in presence of recombinant thioredoxin (rTrx) can reprogram tumor-infiltrating lymphocytes and improve TIL-mediated ACT. The experiments are planned under the following specific aims: 1) To determine if human tumor-derived TILs could be ex vivo programmed with rTRx and exhibit enhanced anti- tumor phenotype, 2) To establish if rTrx TILs are superior to conventional TILs in controlling tumor growth in vivo. We believe that our studies are innovative and will uncover essential aspects that need to be considered when generating tumor-specific Tcm/Tscm cells for the ACT and enhance its wider use by decreasing the prohibitive costs.NARRATIVE Adoptive transfer of T cells that can recognize the tumor and cause tumor cell death is a promising approach. However, many confounding factors such as susceptibility to immunosuppression or T cellsandapos; inability to persist and undergo activation-induced cell death due to chronic antigen stimulation in a tumor microenvironment continue. This application proposes programming tumor-infiltrating T cells, using our approach to increase anti- oxidant capacity of anti-tumor T cells to withstand oxidative tumor microenvironment stress and achieve robust tumor control upon adoptive transfer.