# Targeting lymphoid tissue residency to boost tumor immunotherapies

> **NIH VA I01** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2024 · —

## Abstract

Several current tumor immunotherapies (e.g., PD-1/PD-L1 blockade and tumor vaccine) are designed to boost
endogenous tumor-specific T cell responses. To improve the efficacy of current immunotherapies and benefit
more cancer patients, it is urgent to advance our knowledge about the cellular and molecular mechanisms
underlying the response of endogenous tumor-specific T cells. Importantly, a subset of antigen-specific CD8+ T
cells have been identified as stem cell-like or progenitor-like, which are the ones responding to both PD-1/PD-
L1 blockade and tumor vaccine. However, we know little about how these stem-like T cells respond to tumor
vaccine.
Along a different line of research in mouse acute infection models, tissue-resident memory T cells (TRM) have
been identified as a unique population of memory T cells. In contrast to other migratory T cell subsets, TRMs do
not re-circulate and reside inside a particular tissue (mostly non-lymphoid tissues) for an extended period. We
and others have established a critical role for TGF-b in the establishment of TRM after acute infection. Our
preliminary findings have demonstrated that tumor draining lymph nodes (TDLNs) function as a unique reservoir
to host stem-like tumor-specific CD8+ T cells. Surprisingly, a substantial portion of these TDLN stem-like T cells
adopt a TRM phenotype in a TGF-b-dependent manner. Further, we have discovered that wild type TDLN stem-
like T cells rapidly, but transiently lose TRM phenotype after tumor vaccine. In contrast, TGF-b receptor deficient
TDLN stem-like T cells carry significantly reduced TRM phenotype at baseline and exhibit greatly enhanced and
prolonged response to tumor vaccine. The enhanced response in TDLN is translated into increased migration
from TDLN to tumor and better tumor control for TGF-b receptor deficient CD8+ T cells. Importantly, inhibition of
T cell migration completely abolishes the response to tumor vaccine for TGF-b receptor deficient CD8+ T cells.
Together, our results support a working model that a significant portion of stem-like T cells differentiate into TRM
inside TDLN and will not migrate to tumor site. Loss of tissue-residency is required for stem-like T cells to
differentiate into migratory effectors and elicit robust response to tumor vaccine. Suppression of tissue-residency
in TDLN (e.g., deletion of TGF-b receptor or TGF-b downstream molecular targets) will greatly boost the
differentiation and migration of stem-like T cells, which will lead to better tumor control in response to certain
tumor immunotherapies. In current proposal, we will directly test whether targeting TGF-b or TRM-signature will
boost the migration of stem-like T cells and therefore enhance the efficacy of tumor vaccine as well as local
irradiation released endogenous tumor antigen.
Together, our proposal is primarily focused on the TRM biology of stem-like CD8+ T cells during tumor
immunotherapies, with a special emphasis on TDLN. Our results will have great tra...

## Key facts

- **NIH application ID:** 10721818
- **Project number:** 5I01BX005955-02
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** Nu Zhang
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721818

## Citation

> US National Institutes of Health, RePORTER application 10721818, Targeting lymphoid tissue residency to boost tumor immunotherapies (5I01BX005955-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10721818. Licensed CC0.

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