# Sustaining Tissue Resident Memory T cells

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2022 · $537,503

## Abstract

ABSTRACT
Durable immunity to cancer is sustained by memory T cells. In contrast to circulating memory subsets, which
traffic in and out of the blood, tissue-resident memory (TRM) cells are transcriptionally programed for prolonged
residence and recall function within tissue. Collaborative studies between our laboratories were among the first
to identify a requirement for TRM cells in immunity to cancer. Using a melanoma-associated vitiligo (MAV) mouse
model that closely mimics the vitiligo that develops in immune checkpoint inhibitor-treated melanoma patients
who benefit from prolonged disease-free survival, we showed that skin TRM cells are necessary and sufficient for
long term protective immunity against melanoma in the dermis. However, mechanisms for controlling TRM cell
persistence and identity as well as the contribution of TRM cells to tumor immunity at sites of frequent metastasis
remain unclear. In this application, we examine an unexpected mechanism for TRM cell maintenance in the skin
and reveal a new subset of vitally important TRM cells that persist in tumor-draining lymph nodes.
In the skin of mice with MAV, as well as melanoma patients with vitiligo, immunofluorescent imaging revealed
that TRM cells form lymphoid aggregates containing large populations of CD11c-expressing myeloid cells. While
prior work indicates that CD11c+ dendritic cells (DCs) are critical for initiating immune responses but dispensable
for reactivating TRM we find that depletion of CD11c-expressing cells results in rapid disaggregation and loss of
CD8 TRM cells in the skin. We further show that the CXCR6/CXCL16 axis is required for TRM cell persistence and
tumor protection in the skin. These findings identify a critical requirement for CXCL16-expressing myeloid cells
in coordinating the organization and retention of CXCR6-expressing TRM in the tissue, which will be examined in
Specific Aim 1. The importance of the CXCR6/CXCL16 axis and persisting self antigen in controlling TRM cell
function and plasticity will be tested in Specific Aim 2. Finally, parallel mechanisms will be explored in lymph
nodes (LNs) where our preliminary studies led us to discover a novel population of tumor-specific T cells that is
crucial for protection against melanoma growth in lymph nodes. The presence of LN TRM cells has not previously
been shown in the setting of cancer. A role for APCs and chemokines in maintaining such responses is
essentially unknown, and will be the focus of Specific Aim 3. This proposal will thus test the overarching
hypothesis that tumor-specific TRM cells— both in skin and draining lymph nodes—rely on key interactions with
APCs and chemokines for their proper positioning, maintenance, and anti-tumor function.

## Key facts

- **NIH application ID:** 10389592
- **Project number:** 1R01CA254042-01A1
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Yina Hsing Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $537,503
- **Award type:** 1
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10389592

## Citation

> US National Institutes of Health, RePORTER application 10389592, Sustaining Tissue Resident Memory T cells (1R01CA254042-01A1). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10389592. Licensed CC0.

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