# Targeting T Cell Senescence and Dysfunction for Anti-tumor Immunity

> **NIH NIH R01** · SAINT LOUIS UNIVERSITY · 2021 · $167,231

## Abstract

PROJECT SUMMARY/ABSTRACT
Current immunotherapy strategies, including immune checkpoint blockade therapy targeting CTLA-4 and/or
PD1/PD-L1, have yielded promising results in certain types of cancer patients. However, the overall success
rates of these strategies still vary from 15% to 35%, which suggests that there are other mechanisms and/or
checkpoint signaling involved that are unresponsive to therapy mediated by malignant tumors. Thus,
alternative novel strategies targeting more specific checkpoint molecules or interrupting tolerogenic pathways
are urgently needed. It is now well recognized that the suppression and dysfunction of tumor-reactive T cells
induced by regulatory T cells (Treg) in the tumor suppressive microenvironment present a major barrier for
successful anti-tumor immunotherapy. We recently discovered a novel suppressive mechanism whereby
human Treg cells induce senescence in effector T cells that then exhibit potent suppressive activity and
amplify immune suppression. Therefore, a better understanding of the cellular and molecular processes that
control Treg-induced senescence in effector T cells is essential for the development of effective strategies to
treat human cancer. We identified significantly increased activation of the energy sensor AMPK and dys-
regulation of lipid metabolism in Treg-induced senescent T cells. Furthermore, ATM-associated DNA damage
response and MAPK signaling were selectively involved in T cell senescence mediated by human Treg cells.
In addition, we have discovered that human Toll-like receptor 8 (TLR8) signaling reverses the suppressive
function and prevents the induction of T cell senescence mediated by both naturally occurring Treg and tumor-
derived Treg cells. The central hypotheses of this proposal are that: 1) Human Treg cells can selectively
modulate molecular programs that rewrite T cell lipid metabolism in treated naïve/effector T cells, resulting in
their differentiation into senescent T cells; 2) Senescent and dysfunctional tumor-specific T cells can be
rejuvenated via checkpoint blockages of ATM and MAPK signaling in responder T cells, combined with TLR8
signaling activation in Treg cells, resulting in enhanced anti-tumor immune responses. Specific Aim 1 seeks to
identify the molecular mechanism(s) responsible for the induction of senescence and dysfunction in responder
T cells after interaction with Treg cells. We will dissect how Treg cells molecularly rewrite effector T cell fate
and lipid metabolism. Aim 2 will test the novel concept and strategy that TLR8-mediated reprogramming of
glucose metabolism in Treg cells combined with checkpoint blockage of selective MAPK and/or ATM-
associated DNA damage signaling in responder T cells can synergistically enhance anti-tumor immunity
through reversing the senescence and dysfunction of tumor-specific T cells. A positive outcome of these
studies should lead to novel strategies to reprogram Treg metabolism and control the fate and function of...

## Key facts

- **NIH application ID:** 10107793
- **Project number:** 5R01CA242188-02
- **Recipient organization:** SAINT LOUIS UNIVERSITY
- **Principal Investigator:** Guangyong Peng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $167,231
- **Award type:** 5
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107793

## Citation

> US National Institutes of Health, RePORTER application 10107793, Targeting T Cell Senescence and Dysfunction for Anti-tumor Immunity (5R01CA242188-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10107793. Licensed CC0.

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