# Elucidating the Regulation and Requirement of the NAD salvage pathway in CD8+ T Cell Exhaustion

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2021 · $46,036

## Abstract

Project Summary
The development of checkpoint based cancer immunotherapy has revolutionized cancer treatment in the last
decade. Although many otherwise untreatable patients have seen long term benefit from these therapies, the
long-term benefit for most patients is minimal, highlighting a need for improved treatments. A major goal of
checkpoint based therapies is to reinvigorate chronically stimulated, “exhausted” CD8+ T cells to kill the tumor.
Likewise, a thorough understanding of these chronically stimulated cells and their reinvigoration as compared
to acutely stimulated effector CD8+ T cells will continue to be necessary for future therapeutic discovery. It has
increasingly become appreciated that in addition to epigenetic and transcriptional changes, cell metabolism
plays a critical role in facilitating and determining T cell fate. However, the specific metabolic requirements for
exhausted CD8+ T cells before and after checkpoint based treatment remain unclear. My preliminary studies
suggest that the NAD salvage pathway is a novel mediator of T cell activation and differentiation, which
could be leveraged therapeutically in the context of checkpoint blockade. My data shows that 1) the NAD
salvage pathway is regulated in CD8+ T cells through stimulation of both the TCR and CD28, whose signaling
is known to drive cell fate determination; 2) The NAD salvage pathway is differentially required throughout the
activation of naive CD8+ T cells. During the T cell exit from quiescence, activity of the rate limiting enzyme,
NAMPT, is required for cell survival, proliferation, and function, but not after. I thus hypothesize that that the
NAD salvage pathway is differentially regulated and required in the context of chronic versus acute
antigen stimulation. In this proposal I seek to address this hypothesis by elucidating the specific signaling
mechanisms that induce this pathway in CD8+ T cells (Aim 1) and determining how this pathway is regulated
and required in the context of exhaustion (Aim 2). Completion of these aims will elucidate how different CD8+ T
cell subsets regulate and require the NAD salvage pathway and will mechanistically inform the design of future
immunotherapies designed to reinvigorate exhausted T cells.

## Key facts

- **NIH application ID:** 10233494
- **Project number:** 1F31CA261156-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Lucien Turner
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10233494

## Citation

> US National Institutes of Health, RePORTER application 10233494, Elucidating the Regulation and Requirement of the NAD salvage pathway in CD8+ T Cell Exhaustion (1F31CA261156-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10233494. Licensed CC0.

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