# Role of autocrine cholinergic signaling in maintaining memory T cell responses in oral squamous cell carcinoma

> **NIH NIH R03** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $169,500

## Abstract

PROJECT SUMMARY
Response to immunotherapy remains less than 20% for Oral Cavity Squamous Cell Carcinoma (OSCC). The
poor response is in part due to dysfunctional cytotoxic T cell activity resulting from terminal exhaustion as a
response to chronic exposure to tumor antigen. New strategies are needed to sensitize OSCC to
immunotherapy to improve response rates and overall survival. Neurotransmitters of the parasympathetic
nervous system, such as Acetylcholine (Ach), can be secreted from non-neuronal tissues, including
lymphocytes, which are abundant in microenvironment of OSCC. These lymphocytes express choline
acetyltransferase (ChaT), the enzyme catalyzing the rate limiting step of Ach production. Ach binds to two
classes of receptors, muscarinic and nicotinic receptors, to mediate downstream responses. Stimulation of
muscarinic receptors by Ach restrains pancreatic and breast cancer but promotes gastric and late stage
prostate cancer. The contribution of Ach signaling to the promotion of OSCC is poorly understood. The goal of
this proposal is to elucidate the role of Ach signaling in maintaining homeostasis of T lymphocytes in the tumor
immune microenvironment in OSCC. Preliminary studies have uncovered a putative autocrine pathway of
signaling from Ach secreting CD8+T cells via the cholinergic muscarinic receptor-1 (CHRM1) supporting the
central hypothesis that autocrine Ach-CHRM1 signaling by ChaT+ CD8+ T cells sustains the OSCC anti-tumor
immune response by replenishing the memory T cell pool. The central hypothesis will be tested by pursuing
two specific aims: 1. determine if loss of lymphocyte derived Ach and muscarinic signaling promotes OSCC
growth and impairs T cell infiltration into the tumor immune microenvironment (TIME) and 2. determine if
autocrine Ach-CHRM1 signaling on T lymphocytes maintains long-term activation potential and prevents
exhaustion by maintaining the memory T cell pool. In the first aim the effect of targeted disruption of the Ach-
CHRM1 pathway in CD8+T cells on orthotopic OSCC tumor growth kinetics will be evaluated. Topography of
the TIME will be analyzed using quantitative multiplex immunofluorescence. For the second aim ex vivo
activation and proliferation assays will be used to asses T cell dysfunction longitudinally over the course of
tumor progression in OSCC models with targeted disruption of Ach-CHRM1 signaling in CD8+ T lymphocytes.
The proposed research examines a role for non-neuronal, lymphocyte derived, Ach in maintaining anti-tumor
immune responses by maintaining the memory T cell pool and preventing terminal exhaustion that can lead to
failure of immunotherapy treatment.

## Key facts

- **NIH application ID:** 10987548
- **Project number:** 1R03DE033467-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Ruth A White
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $169,500
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10987548

## Citation

> US National Institutes of Health, RePORTER application 10987548, Role of autocrine cholinergic signaling in maintaining memory T cell responses in oral squamous cell carcinoma (1R03DE033467-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10987548. Licensed CC0.

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