# Excessive lipid metabolism in T cell senescence and immunosuppression

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $388,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Current immunotherapies, including immune checkpoint blockage therapy and adoptive T cell therapy, have
resulted in promising results in certain types of cancer patients. However, these immunotherapies have so far
been insufficient to reproducibly eliminate tumors. It is clear that tumor-reactive T cells are suppressed and
dysfunctional in the suppressive tumor microenvironment that is a major obstacle for successful tumor
immunotherapy. Thus, dissecting the distinct mechanisms responsible for T cell dysfunctional states within the
suppressive tumor microenvironment should provide novel avenues for tumor immunotherapy.
 We discovered that induction of T cell senescence is an important T cell dysfunctional state and a novel
suppressive mechanism utilized by both human naturally occurring and tumor-derived regulatory T (Treg) cells
in the tumor microenvironment. In fact, significant accumulation of senescent CD8+ T cells has also been found
in the tumor-infiltrating T cells (TILs) from various types of cancer patients. Importantly, we found that these
senescent T cells are functionally suppressive and molecularly distinct from anergic and exhausted T cellsand
that they are a critical mediator and amplifier for immune suppression within the tumor microenvironments.
Therefore, a better understanding of this novel suppressive mechanism and the molecular processes in
responder T cells suppressed by Treg cells is essential for the development of effective strategies to treat
human cancers. Cellular energy metabolism directs T cell survival, proliferation and their specific functions.
Different T cell subsets have different metabolic profiles. We have more recently identified that Treg-induced
senescent T cells exhibit active lipid metabolism, resulting in upregulation of lipid metabolic enzymes and
secretory lipid species, and accumulation of lipid droplets (LDs). The central hypotheses of this proposal are
that: 1) Excessive lipid metabolism is critical for senescence development and immunosuppression of effector
T cells mediated by Treg cells; 2) Senescent and dysfunctional tumor-specific T cells can be rejuvenated via
lipid reprogramming for enhanced anti-tumor immunity. Specific Aim 1 seeks to identify whether the excessive
lipid metabolism is involved in senescence development and immunosuppression of T cells induced by Treg
cells. Specific Aim 2 will explore the novel concept and develop effective strategies to overcome senescent
and exhausted tumor-specific T cells via lipid metabolism reprogramming combined with selective checkpoint
blockage therapy of anti-PDL1 for enhanced anti-tumor efficiency in the adoptive T cell transfer therapy tumor
models. The positive outcome of these studies should lead to novel strategies to reprogram lipid metabolism
and effector functions of tumor-specific T cells for cancer treatments.

## Key facts

- **NIH application ID:** 10898921
- **Project number:** 5R01AI173260-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Guangyong Peng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2023-08-03 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898921

## Citation

> US National Institutes of Health, RePORTER application 10898921, Excessive lipid metabolism in T cell senescence and immunosuppression (5R01AI173260-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10898921. Licensed CC0.

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