# Regulatory T cells in cancer therapy

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $634,434

## Abstract

Project Summary
Extensive studies have been conducted to define the development, conversion, stability, and regulatory
mechanisms of CD4+Foxp3+ regulatory T cells (Tregs) in homeostasis and a variety of disease models. It is
well-known that Tregs are recruited, converted, and expanded in the tumor microenvironment and act as one
of the major immunosuppressive mechanisms dampening spontaneous tumor-associated antigen (TAA)-
specific T cell immunity and immunotherapy and active vaccination induced anti-tumor immunity. However, how
Tregs behave in the metabolically abnormal tumor microenvironment remains unknown.
The Warburg effect is an important metabolic feature in many types of cancer. Given that nutrients including
glucose are poorly replenished in the tumor, it is assumed that T cell glycolytic metabolism has been altered
due to the Warburg effect in the tumor microenvironment. In support of this, poor glycolysis can alter effector
memory T cell function in the tumor microenvironment. In addition, the oxygen-sensing prolyl-hydroxylase
proteins, necrotic cells released potassium ions, and abnormal zinc metabolism can impair effector T cell
function in the tumor microenvironment. These studies underscore the significance of metabolic regulation of
memory T cells in the tumor.
Tregs exhibit a memory and effector phenotype in the human tumor microenvironment. It is unknown whether
Tregs are subject to glycolytic regulation in the tumor. Furthermore, oxidative stress is an additional metabolic
feature in the tumor microenvironment. Myeloid dendritic cells (DCs) are phenotypically and functionally altered
by oxidative stress in the tumor microenvironment. However, it is unknown whether oxidative stress alters Treg
phenotype and function in the tumor and affects cancer immunotherapy. To address these questions, we have
examined the phenotypic and functional nature of Tregs in human ovarian cancer and several types of mouse
cancer. We have found that Tregs are highly apoptotic in the tumor microenvironment. Interestingly, apoptotic
Tregs are superior suppressors via a distinct mechanism. Furthermore, oxidative stress, rather than glycolysis,
is a metabolic mechanism controlling tumor Treg functional behavior and tempering therapeutic efficacy of
immune checkpoint therapy. This project is to conduct comprehensive molecular, functional, translational, and
clinical research on the nature of Tregs and their metabolic pathway in the cancer microenvironment. We will
provide rich opportunities to take our understanding of Treg biology in the tumor to a new level of basic and
practical application. Our specific aims are:
Aim 1 is to test our hypothesis that oxidative stress controls Treg apoptosis in the tumor
microenvironment. Aim 2 is to determine the molecular mechanisms controlling the energy circuit
of Tregs and the interaction between Tregs and APCs in tumor.

## Key facts

- **NIH application ID:** 10361528
- **Project number:** 5R01CA244827-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** WEIPING ZOU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $634,434
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10361528

## Citation

> US National Institutes of Health, RePORTER application 10361528, Regulatory T cells in cancer therapy (5R01CA244827-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10361528. Licensed CC0.

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