# Tumor-infiltrating T cell metabolic dysfunction and genetic reprogramming for effective immunotherapy

> **NIH NIH K00** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $92,043

## Abstract

Abstract
Tumor-infiltrating T cell metabolic dysfunction and genetic reprogramming for effective immunotherapy
The ability to target and destroy mutated cells is an essential characteristic of the immune system. Despite this
attribute, the immune system largely fails to eliminate cancer once a tumor is established. This is due in part to
the immunosuppressive nature of the tumor microenvironment (TME), which inhibits CD8+ tumor infiltrating T
lymphocytes (CD8+ TIL) from becoming activated and killing their target cells. While it is known that the TME
can directly inhibit CD8+ TIL through receptor-ligand interactions and suppressive cytokines to cause
phenotypically and functionally exhausted T cells, it is increasingly understood that the TME is also
metabolically suppressive. Tumor cells utilize an abundance of metabolites due to their proliferative nature,
creating an additional suppressive mechanism for CD8+ TIL, as they need adequate nutrients for effector
functions and to fuel their own proliferative nature. In this NCI Predoctoral to Postdoctoral Fellow Transition
Award (F99/K00) application, the metabolic deficiencies of CD8+ TIL are described, showing CD8+ TIL
experience significant loss of mitochondrial mass and function. This is due to repression of mitochondrial
biogenesis transcription factor PGC1α, due to chronic Akt activation in TIL. When PGC1α was overexpressed
in CD8+ TIL, it not only led to increased mitochondria, but improved TIL effector function and decreased tumor
burden. These results led to the proposed studies: to further understand why mitochondria are important to TIL
function. It is hypothesized that mitochondria are the defining organelle between a functional memory T cell
and a dysfunctional exhausted T cell. To explore this hypothesis, T cells will be rendered metabolically-
deficient in vitro through pharmacologic depletion of mitochondrial function. These metabolically deficient T
cells (called Rho0 T cells) will be used to explore how mitochondria may be essential for calcium buffering to
limit NFAT and an exhaustion genetic profile, as well as how mitochondria may be required for preventing an
exhaustion epigenetic profile. After the completion of these studies, the applicant will transition to postdoctoral
studies, where they will further explore TIL dysfunction, but with the goal of a translational, therapeutic
outcome. The applicant will study how chimeric antigen receptor (CAR) T cells may be improved upon and
used therapeutically in human T cells. Understanding how T cells become dysfunctional in cancer is important
for both our understanding of T cell biology, and for improving targeted cancer immunotherapy.

## Key facts

- **NIH application ID:** 10347320
- **Project number:** 5K00CA222711-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Nicole E Scharping
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $92,043
- **Award type:** 5
- **Project period:** 2020-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10347320

## Citation

> US National Institutes of Health, RePORTER application 10347320, Tumor-infiltrating T cell metabolic dysfunction and genetic reprogramming for effective immunotherapy (5K00CA222711-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10347320. Licensed CC0.

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