# Metabolic barriers to T cell activation in clear cell renal cell carcinoma

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $511,194

## Abstract

SUMMARY
 Exploiting immunity to eliminate cancer cells offers tremendous new therapeutic opportunities, including the
widely employed immune checkpoint blockade (ICB) agents. These approaches are challenged, however, by
the multitude of mechanisms through which tumors can suppress anti-tumor immunity and render them effective
in only a portion of patients. We have shown that effector T cells require high rates of glucose uptake for anabolic
metabolism, and it is now apparent that cancer cells and the tumor microenvironment (TME) disrupt anti-tumor
immunity in part through metabolic immune suppression. To address this barrier to immunotherapy, we
examined tumor infiltrating lymphocytes (TIL) from surgically excised samples of human clear cell Renal Cell
Carcinoma (ccRCC), a cancer with moderate rates of ICB response that is characterized by loss of the Von
Hippel-Lindau (VHL) tumor suppressor. These tumors allowed us to show that both glucose and glutamine are
available in the TME and while glucose metabolism promotes effector T cells, metabolism of glutamine restrains
T cell effector function. It is unclear which glutamine-dependent enzymes or metabolites suppress T cells, but
we found that Glutaminase-deficiency altered histone methylation and reduced expression of Pik3ip3, a PI3K-
inhibitory protein that suppresses PI3K/mTORC1 signaling and production of inflammatory effector cytokines.
To further explore mechanisms of T cell suppression by glutamine, we performed an in vivo CRISPR screen in
primary TIL and found loss of Glutamine Synthetase among all glutamine-metabolizing enzymes to most
effectively increase TIL accumulation. We also directly defined cell type-specific glucose and glutamine usage
in the TME using radiolabeled Positron Emission Tomography tracers. In contrast to classic Warburg
metabolism, tumor associated macrophages (TAM) were the dominant consumers of glucose, followed by TIL,
and cancer cells, which instead preferentially consumed glutamine. Interestingly, loss of Vhl did not increase
glucose uptake of RCC cells in vivo but instead increased glucose uptake in TIL and TAM. To explore these
pathways in patients undergoing ICB therapy, we next performed high dimensional CyTOF analyses of
peripheral blood from a longitudinal cohort of patients before and 3 weeks after start of therapy. This approach
specifically identified rare but highly proliferative ICB-responsive CD8 and CD4 T cells with elevated
mitochondrial potential. Based on these findings, we hypothesize that RCC genetics drive a metabolically
immunosuppressive TME with abundant glutamine that suppresses PI3K signaling to impair T cell
effector differentiation and function. We will study primary human ccRCC tumors and mouse RCC models to:
(1) Test how nutrients in the ccRCC TME and tumor genetics influence TIL function and metabolism; and (2)
Determine how glucose and glutamine metabolism in the TME promote or suppress anti-tumor immunity.
Together, these studies wil...

## Key facts

- **NIH application ID:** 10788307
- **Project number:** 5R01CA217987-07
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Jeffrey C Rathmell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $511,194
- **Award type:** 5
- **Project period:** 2018-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10788307

## Citation

> US National Institutes of Health, RePORTER application 10788307, Metabolic barriers to T cell activation in clear cell renal cell carcinoma (5R01CA217987-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10788307. Licensed CC0.

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