# Metabolic Control of Innate and Adaptive Immunity in Breast Cancer

> **NIH NIH R01** · SAINT LOUIS UNIVERSITY · 2021 · $93,461

## Abstract

PROJECT SUMMARY/ABSTRACT
Immunotherapy is a promising approach for treating patients with advanced breast cancer. However,
immunosuppressive microenvironments induced by regulatory T cells (Treg) present a major barrier to
successful anti-tumor immunotherapy. Defining the suppressive mechanisms used by different types of tumor-
infiltrating Treg cells is essential for the development of novel strategies to treat human breast cancer. We
recently discovered high percentages of  Treg cells existing among the tumor-infiltrating lymphocytes (TILs)
of breast tumor patients, which are strongly negatively correlated with clinical outcomes. We further identified a
novel suppressive mechanism whereby  Treg cells induce senescence in T cells and dendritic cells (DCs)
that then also develop potent suppressive activity. Therefore, it is critical to further identify the molecular
mechanisms responsible for  Treg-induced senescence in immune cells, and then to develop strategies to
reverse senescence induction mediated by  Treg cells. Increasing evidence indicates that the ability of a
lymphocyte to perform functional immune responses is controlled by pathways of energy metabolism.
However, little is known about the regulation of energy metabolism in tolerogenic DCs and Treg cells. We
recently found that  Treg cells dramatically reprogram DC lipid metabolism. In addition, we observed that
TLR8 signaling significantly suppresses glucose metabolism in human  Treg cells via inhibition of both
glucose transporters and glycolysis-related enzymes. The central hypotheses of this proposal are that: 1)
breast cancer-derived Treg cells rewrite lipid metabolism in DCs, resulting in DC senescence with
tolerogenic phenotypes and functions; 2) reprogramming of metabolism in Treg cells and DCs can serve as a
novel strategy to synergistically enhance anti-tumor immunity for tumor immunotherapy. Specific Aim 1 seeks
to identify what lipid species are changed in  Treg-induced senescent DCs and whether the altered lipid
components are causatively related to the DC senescence and impaired functions. We will then investigate the
importance of transcription factor STAT and PD1-PDL1 signaling in controlling lipid metabolism disorder,
senescence induction and impaired functions occurred in  Treg-treated DCs. Specific Aim 2 will identify the
key glucose metabolites that involve  Treg-mediated immune suppression and are regulated by TLR8
signaling for functional reversal in human  Treg cells. We will then test the novel concept that TLR8
activation in  Treg cells combined with checkpoint blockade of PD-L1 in DCs can serve as novel strategies to
reprogram their metabolism and synergistically enhance anti-tumor immunity for breast cancer immunotherapy.
A positive outcome from these studies should lead to novel strategies to reprogram innate and adaptive
immune cell metabolism for future breast cancer immunotherapy.

## Key facts

- **NIH application ID:** 10104462
- **Project number:** 5R01CA237149-02
- **Recipient organization:** SAINT LOUIS UNIVERSITY
- **Principal Investigator:** Guangyong Peng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $93,461
- **Award type:** 5
- **Project period:** 2020-02-11 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104462

## Citation

> US National Institutes of Health, RePORTER application 10104462, Metabolic Control of Innate and Adaptive Immunity in Breast Cancer (5R01CA237149-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10104462. Licensed CC0.

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