# TCR signaling and cell cycle regulation in tumor-specific CD8 T cell dysfunction

> **NIH NIH R37** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $580,177

## Abstract

PROJECT SUMMARY
T cells have the potential to recognize and eliminate cancer cells. However, most often cancers progress in spite
of the tumor-specific T cells present within tumors. While current immunotherapies such as immune checkpoint
blockade can bring about long-lasting remissions in some patients with certain cancer types, most patients are
not cured. Using a genetic liver cancer mouse model, we previously demonstrated that tumor-specific T cells,
after entering malignant livers, rapidly differentiate to an early and then late dysfunctional state, encoded by
distinct epigenetic programs. Late dysfunctional tumor-specific T cells failed to become functional again in
response to immune checkpoint blockade, and we found that human tumor-infiltrating lymphocytes from patients
with solid tumors shared key epigenetic hallmarks of late dysfunctional T cells from our mouse liver cancer
model. Thus, a critical challenge for cancer immunotherapy is how to prevent or revert tumor-specific T cells
from entering this epigenetically-enforced dysfunctional state. We now find that late TST fail to proliferate in
response to T cell receptor stimulation, and we hypothesize that the barrier to functional rescue of late
dysfunctional tumor-specific T cells is their inability to enter cell cycle in response to TCR stimulation. We will
leverage our preclinical mouse cancer models and study TIL in liver and breast tumors from human patients to
(i) understand how cell cycle kinetics and T cell receptor signaling defects change during dysfunctional
differentiation, (ii) define how cell cycle and epigenetic changes determine functional rescue, and (iii) test
strategies to overcome cell cycle and TCR signaling defects in late dysfunctional T cells. These studies will
uncover critical insights into how cell cycle and T cell receptor signaling regulate the T cell epigenome and test
therapeutically-applicable strategies to overcome barriers to tumor-specific T cell reprogramming, which may
lead to improved cancer immunotherapies.

## Key facts

- **NIH application ID:** 10446019
- **Project number:** 1R37CA263614-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Mary Philip
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $580,177
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446019

## Citation

> US National Institutes of Health, RePORTER application 10446019, TCR signaling and cell cycle regulation in tumor-specific CD8 T cell dysfunction (1R37CA263614-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10446019. Licensed CC0.

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