# Targeting metabolic checkpoints in the tumor microenvironment to boost efficacy of anti-CTLA-4

> **NIH NIH R21** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $161,494

## Abstract

PROJECT SUMMARY/ABSTRACT
Anti-CTLA-4 was first immune checkpoint blockade therapy approved by the FDA to treat patients with cancer.
Notwithstanding its impressive clinical response in ~20% of patients with advanced melanoma, there is a clear
need to improve its efficacy. We recently showed that loss of IFN- signaling genes could partially explain why
the remaining ~80% patients are resistance to anti-CTLA-4 therapy. Therefore, identifying novel therapeutic
targets/approaches capable of overcoming resistance and boosting efficacy of anti-CTLA-4 is of utmost
importance We and others previously demonstrated that the HIF1-glycolysis axis orchestrates an essential
“metabolic checkpoint” in driving effector T cell differentiation and in suppressing regulatory T cell induction, two
functional outcomes closely associated with anti-CTLA-4 efficacy, suggesting activating HIF1 and glycolysis in
T cells could represent an effective approach to improve therapeutic efficacy of anti-CTLA-4. To this end, we
have generated interesting preliminary data showing that anti-CTLA-4 selectively upregulates HIF1 and its
downstream targets, glycolytic enzymes in tumor-infiltrating T cells (TILs). And, specific deletion of HIF1 in T
cells and simultaneous inhibition of glycolysis largely abolishes the therapeutic effects of anti-CTLA-4, pointing
to a critical role of HIF1 and glycolysis in this therapy. Therefore, we propose that HIF1, via modulating
glycolytic activity of TILs, dictates therapeutic efficacy of anti-CTLA-4, which can serve as novel therapeutic
targets to promote efficacy of anti-CTLA-4. In Aim 1, we will characterize how T cell-intrinsic HIF1 governs
glycolytic activity and effector functions of TILs in response to anti-CTLA-4. In Aim 2, we will target the HIF1-
glycolysis pathway to promote therapeutic efficacy of anti-CTLA-4. While it is well-known that anti-CTLA-4
markedly rejuvenates effector functions of TILs, the specific underlying mechanisms are largely unknown.
Insights gained from these studies will significantly advance our understanding of how anti-CTLA-4 metabolically
augments anti-tumor responses and manifest novel therapeutic opportunities (e.g., targeting metabolic
pathways) to improve efficacy of anti-CTLA-4.

## Key facts

- **NIH application ID:** 9872994
- **Project number:** 5R21CA230475-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Lewis Z. Shi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $161,494
- **Award type:** 5
- **Project period:** 2019-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9872994

## Citation

> US National Institutes of Health, RePORTER application 9872994, Targeting metabolic checkpoints in the tumor microenvironment to boost efficacy of anti-CTLA-4 (5R21CA230475-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9872994. Licensed CC0.

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