# Investigating altered T-cell metabolism during chronic antigen encounter

> **NIH NIH K08** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $263,034

## Abstract

PROJECT SUMMARY/ABSTRACT
Despite recent advances in the targeting of immune checkpoints across malignancies, many patients fail to
respond to treatment, suggesting alternative mechanisms of immunosuppression. Metabolic dysfunction within
tumor-infiltrating T-cells has emerged as a potential mechanism by which long-term anti-tumor immunity is
impaired. The mechanism by which altered metabolism suppresses intratumoral T-cell function, however,
remains to be fully characterized. Cellular metabolites not only supply the bioenergetics needs of proliferating
immune cells, but also regulate gene expression by serving as the substrates for chromatin modifications.
Preliminary data presented in this proposal utilize a combination of in vitro and in vivo systems to explore the
metabolic liabilities of T-cells during chronic exposure to tumor antigens. Under these conditions, T-cells
experience high levels of oxidative stress. This compromises the ability of T-cells to oxidize glucose and
glutamine within the TCA cycle, leading to bioenergetic compromise that impairs nucleotide biosynthesis and
alters the availability of substrates for DNA and histone demethylation reactions. Enhancing redox
homeostasis has beneficial effects on anti-tumor T-cell immunity in vitro as well as in vivo. Thus, the efficacy
of T-cells within the tumor microenvironment may be primarily limited by metabolic alterations that generate
redox stress. This hypothesis will be rigorously tested by (1) using a combination of in vitro and in vivo models
of T-cell exhaustion in both mice and primary patient tumors to define the impact of chronic antigen-driven
metabolic alterations on T-cell proliferation, chromatin modifications, and effector function, (2) determining how
cysteine limitation exacerbates T-cell dysfunction within the tumor microenvironment, and (3) determining
whether enhancing redox homeostasis, either by increasing intracellular cysteine availability or limiting the
generation of oxidative stress can reverse metabolic T-cell dysfunction and enhance anti-tumor immunity. The
proposed investigations will expand the armamentarium of strategies to enhance immune responses in cancer,
particularly for the patients who are unresponsive to anti-PD-1 therapy. The applicant, Dr. Santosha Vardhana,
an Assistant Attending with the Lymphoma Service at Memorial Sloan Kettering Cancer Center, has outlined a
5-year career plan that builds on his scientific background in immunology and cellular metabolism as well as
his clinical training in medical oncology and immunotherapy. Dr. Vardhana will conduct the proposed research
under the mentorship of Dr. Craig Thompson, an internationally recognized expert in immunology and
metabolism with a strong track record of training successful physician scientists, with co-mentorship by Dr.
Jedd Wolchok, a highly recognized expert in cancer immunotherapy with significant experience interrogating T-
cell function in both mouse models and primary patient ...

## Key facts

- **NIH application ID:** 10124338
- **Project number:** 5K08CA237731-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** SANTOSHA VARDHANA
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $263,034
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124338

## Citation

> US National Institutes of Health, RePORTER application 10124338, Investigating altered T-cell metabolism during chronic antigen encounter (5K08CA237731-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10124338. Licensed CC0.

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