# ER stress pathways regulate T-cell allogeneic and anti-tumor responses

> **NIH NIH R21** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $218,790

## Abstract

Summary
Unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic
reticulum (ER) stress in response to protein misfolding. Three master regulators control the UPR: IRE1α,
PERK, and ATF6. The primary goal of UPR is to induce transcriptional and translational programs to maintain
ER homeostasis for cell survival. Thus, dysfunctional UPR signaling has been shown to contribute to various
health conditions including metabolic diseases, degenerative diseases, inflammatory disorders, and cancer.
The ER stress pathways have been studied in cancer cells extensively, but have been overall understudied in
T-cell immunity and tolerance. There are several knowledge gaps in understanding the impacts of the ER
stress pathways in T-cell immunity against cancer. Our long-term goal is to develop novel strategies through
targeting the ER stress pathways for improving cancer immunotherapy of human malignancies. the overall
objectives of this application are to provide critical information towards more understanding the impacts of ER
stress pathways on immune responses against cancer, which will eventually help to fulfill our long-term goal.
Our central hypothesis is that the IRE-1α/XBP-1 and PERK/CHOP pathways differentially regulate CD4 and
CD8 anti-tumor responses in microenvironment dependent manner. The hypothesis has been formulated
based on preliminary data generated from in vitro and in vivo experiments using genetically modified mice with
T-cell conditional knock-out (KO) for XBP-1, PERK or both. This hypothesis will be tested in the following two
Specific Aims: 1) To define the role of XBP-1 and PERK in T-cell mediated graft-versus-host (GVH) and graft-
versus-leukemia (GVL) responses; 2) To define the impact of XBP-1 and PERK in T-cell immunity against
tumor. The proposed study is expected to provide a strong guidance for improving T-cell based cancer
immunotherapy by targeting the ER stress pathways and to provide a solid foundation for further studying
underlying mechanisms of ER stress pathways in regulating T-cell immunity.

## Key facts

- **NIH application ID:** 10430505
- **Project number:** 1R21CA263140-01A1
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Xue-Zhong Yu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $218,790
- **Award type:** 1
- **Project period:** 2022-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10430505

## Citation

> US National Institutes of Health, RePORTER application 10430505, ER stress pathways regulate T-cell allogeneic and anti-tumor responses (1R21CA263140-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10430505. Licensed CC0.

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