New strategies to improve adoptive cell therapy (ACT) protocols are emerging to enhance in vivo persistence ofadoptively transferred tumor epitope-specific T cells and overcome tumor-induced immunosuppression. Ourpreliminary 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 withTrx transgenic mouse, or engineering human T cells with a retroviral vector with TCR and Trx together. Thesepreliminary observations led us to hypothesize that "the presence of Trx drives tumor-reactive T cells to a c-SHhiphenotype, which results in increased persistence in the oxidative tumor microenvironment and improved tumorcontrol." We propose to further strengthen the translational aspect of this strategy by determining if strategies toincrease anti-oxidant capacity in presence of recombinant thioredoxin (rTrx) can reprogram tumor-infiltratinglymphocytes 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 invivo. We believe that our studies are innovative and will uncover essential aspects that need to be consideredwhen generating tumor-specific Tcm/Tscm cells for the ACT and enhance its wider use by decreasing theprohibitive costs.
Public Health Relevance Statement: 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 cells' 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.
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