# Metabolic Barriers to T Cell Activation in Clear Cell Renal Cell Carcinoma

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $441,879

## Abstract

SUMMARY
 Exploiting the immune system to eliminate cancer cells has been a goal for many years, but it has become
apparent that tumors actively suppress immune cell functions. While inhibition of immunomodulatory
receptors, such as through PD-1 checkpoint blockade therapy, holds tremendous promise, this treatment is
effective in only a portion of patients. Factors that determine immune responsiveness against tumors remain
largely uncertain. Our data show, however, that the metabolic demands of T cells may be a critical factor in the
success of immunotherapy. We have shown that effector T cell (Teff) activation requires high rates of glucose
and anabolic metabolism yet cancer cells and the tumor microenvironment can inhibit Teff metabolic pathways.
This may represent a fundamental mechanism of tumor-mediated immune suppression. To better understand
the influence of the tumor microenvironment on T cell metabolism and improve immunotherapies, we have
examined tumor infiltrating lymphocytes (TIL) from surgically-excised human clear cell Renal Cell Carcinoma
(ccRCC) tumor samples, a cancer responsive to PD-1 blockade and with a prognostic immune signature.
ccRCC is highly associated with mutations and loss of the Von Hippel Lindau (VHL) tumor suppressor, which
leads to stabilization of HIF1α and HIF2α and induction of a transcriptional pseudo-hypoxic response that
alters the tumor to promote an immune suppressive microenvironment that can negatively impact ccRCC CD8
TIL function and anti-tumor immunity. We found CD8 TIL are abundant in ccRCC, yet these cells are uniformly
PD-1high and functionally suppressed. In addition, CD8 TIL had multiple metabolic impairments and were
unable to efficiently uptake glucose or perform glycolysis and had small, fragmented mitochondria that
produced high levels of Reactive Oxygen Species (ROS). Importantly, neutralization of ROS or provision of
the glycolytic end-product pyruvate could partially rescue ccRCC CD8 TIL function. Glutamine is also a key
nutrient to support mitochondrial metabolism for T cells through glutaminolysis and we report here that
inhibition or genetic deletion of the first enzyme in this pathway, Glutaminase 1 (GLS1), leads to a
compensatory increase in glycolysis that can enhance cytotoxic CD8 function. This proposal will test the
hypothesis that the ccRCC microenvironment impairs glycolysis and leads to accumulation of dysfunctional
mitochondria in CD8 TIL and that rescue of TIL glycolysis will enhance T cell response to immunotherapy. We
will study primary ccRCC tumors and mouse RCC models to: (1) Determine how mitochondria are
dysregulated and impair activation and metabolism of ccRCC CD8 TIL; (2) Investigate if promoting glucose
uptake or inhibiting GLS1 to enhance glucose metabolism can improve the metabolism and function of CD8
TIL; and (3) Test how PD-1 blockade therapy impacts T cell metabolism and functional populations in ccRCC.
Together, these studies will establish the mechanism of m...

## Key facts

- **NIH application ID:** 9880403
- **Project number:** 5R01CA217987-03
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Jeffrey C Rathmell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $441,879
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880403

## Citation

> US National Institutes of Health, RePORTER application 9880403, Metabolic Barriers to T Cell Activation in Clear Cell Renal Cell Carcinoma (5R01CA217987-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9880403. Licensed CC0.

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