# Anti-oxidant and Metabolic Phenotype in Regulating Tumor Specific T cell Memory Response

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $485,903

## Abstract

ABSTRACT
New strategies to improve adoptive cell therapy (ACT) protocols are now 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 its anti-oxidant capacity. Overexpression of thioredoxin-1 (Trx), a key
molecule that regulates cell-surface thiols (c-SH), resulted in increased Tcm phenotype in T cells obtained from
TCR transgenic mouse crossbred with Trx transgenic mouse, or engineering human T cells with retroviral
vector with TCR and Trx together. Further, a quantification of the metabolites within Pmel vs. Pmel-Trx cells
showed that metabolites from pentose-phosphate pathway (PPP) and tricarboxylic acid cycle (TCA)
intermediate alpha-ketoglutarate (α-KG) were significantly higher in Pmel-Trx T cells as compared to Pmel
cells. While reductive intermediates generated by PPP are important to overcome oxidative stress, recent
reports have shown that α-KG is important in extending the cellular lifespan and regulating pluripotency of
stem cells. These preliminary observations lead us to hypothesize that “the presence of Trx drives tumor
reactive T cells to a c-SHhi phenotype, which not only exhibits enhanced anti-oxidant phenotype, but regulates
a combination of events including post-translational modifications, and epigenetic stability that lead to
metabolically fit anti-tumor T cells”. We propose the following specific aims: 1) To determine how the level of
thiol/thioredoxin on the surface of T cells regulates the generation of tumor reactive Tcm/Tscm cells in vivo, 2)
To determine how changes in the metabolic pathways and metabolites in T cells regulate the generation of
tumor reactive Tcm/Tscm in vivo, 3) To determine if modulation of reduced thiols and/or metabolites results in
generation of tumor reactive TCR transduced human T cells with functional memory phenotype. We believe
that our studies are innovative and will uncover important aspects that need to be considered when generating
tumor specific Tcm/Tscm cells for ACT.

## Key facts

- **NIH application ID:** 10741787
- **Project number:** 5R01CA236379-05
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Shikhar Mehrotra
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $485,903
- **Award type:** 5
- **Project period:** 2019-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10741787

## Citation

> US National Institutes of Health, RePORTER application 10741787, Anti-oxidant and Metabolic Phenotype in Regulating Tumor Specific T cell Memory Response (5R01CA236379-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10741787. Licensed CC0.

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