# Mechanisms underlying tumor-infiltrating tissue resident memory T cell generation and maintenance

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $274,969

## Abstract

Project Summary/Abstract
Immunotherapy is rapidly becoming a mainstream treatment of cancers, nonetheless, less than 30% of
patients benefit from this approach. Thus, there is an urgent need to develop novel immunotherapeutic agents
for patients who do not respond to currently available immunotherapies. Our goal is to identify such novel
targets by investigating the molecular mechanisms that drive the generation and maintenance of a distinct
class of tumor-infiltrating cytotoxic T lymphocytes (CTLs)—tissue-resident memory cells (TRM). We recently
performed the largest unbiased survey of over 100 transcriptomes from purified CD8+ CTLs isolated from
tumors of treatment-naïve patients with early-stage lung cancer and provocatively showed that TRM were key
players in mediating robust anti-tumor immune responses (Nature Immunology 2017). We revealed that TRM
was selectively enriched in tumors with a high density of tumor-infiltrating lymphocytes (TILs) and displayed
enhanced cytotoxicity and proliferation, implying better anti-tumor activity. We also showed that a higher
density of TRM cells in tumors predicted better survival outcomes. Given that only a subset of tumors is
enriched for TRM, which mounts an effective anti-tumor response, it is crucial to understand the key signals that
drive TRM cell generation and maintenance within tumors. We hypothesize that TRM development likely involves
several molecular switches (like transcription factors) that regulate migration, tissue retention, survival and
response to local milieu (tumor). Here, we propose to directly analyze the transcriptome and epigenome of
tumor-infiltrating TRM CTLs to define the molecular pathways governing TRM development by utilizing genomic
tools such as single-cell sequencing, ATAC-sequencing and histone ChIP-Seq. We will also functionally
validate the role of one such important candidate pathway, i.e., CD39 signaling, in promoting TRM, given that
our recent studies show differential high expression of CD39 on TRM-rich TILs. CD39 has been associated with
immunesuppression as well as T memory formation, hence the consequences of CD39 expression are
unclear. Given that tumor-infiltrating TRM mount clinically beneficial anti-tumor immune responses, we
hypothesize that higher expression of CD39 on TRM cells may preferentially protect them from ATP-induced cell
death and enable persistence within tumors. We will evaluate the functional role of CD39 in vivo in the
generation and maintenance of tumor-infiltrating TRM by testing effects of CD39 abrogation utilizing
transplantable and autochthonous mouse tumor models and CD8+ T cell-specific CD39-knockout mice.
Furthermore, CD39 knock-down or overexpression studies will be performed in patient-derived tumor-
infiltrating TRM cells in vitro and the effects on TRM activation, apoptosis, proliferation, cytotoxicity and cytokine
production will be evaluated. In summary, our studies will provide important insights into the molecular signals
t...

## Key facts

- **NIH application ID:** 9906191
- **Project number:** 5K08CA230164-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Anusha Preethi Ganesan
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $274,969
- **Award type:** 5
- **Project period:** 2019-04-03 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906191

## Citation

> US National Institutes of Health, RePORTER application 9906191, Mechanisms underlying tumor-infiltrating tissue resident memory T cell generation and maintenance (5K08CA230164-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9906191. Licensed CC0.

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