# Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $569,160

## Abstract

PROJECT SUMMARY
As a ubiquitous HSP90 paralog in the endoplasmic reticulum (ER), GRP94 plays important roles in protein quality
control in the secretory pathway by participating in both the unfolded protein response and the ER-associated
protein degradation pathway. My laboratory has demonstrated that GRP94 is a strategically important target for
cancer, because it controls multiple key molecular pathways in cell growth, migration, immune tolerance and
differentiation, including integrins, TLRs, IGF-II, Wnt co-receptor LRP6, and GARP (or LRRC32). GARP
(Glycoprotein A Repetitions Predominant) is responsible for surface docking and activation of latent TGFb and
a focus of this proposal We have made significant contributions to this area through immunological and
biochemical studies, including: 1) that GARP is an important molecule for cancer immune evasion via regulating
multiple cell types (e.g., cancer cells, platelets, regulatory T cells, B cells). 2) We discovered a novel mechanism
of TGFb activation from cell surface GARP-TGFb complex via proteolytic cleavage of GARP. 3) GARP has been
found to be aberrantly expressed in multiple human cancers to promote oncogenesis via both cancer cell-intrinsic
and -extrinsic mechanisms. 4) Preclinical studies suggest that GARP is a novel therapeutic target for cancer
immunotherapy. These accomplishments have deepened our conviction that the study of GRP94 and its client
network will lead to better understanding of this chaperone biology in cancer and to development of novel cancer
therapeutics, alone or in combination with approved immunotherapeutic agents. In the next phase of the study,
we will address the hypothesis that GRP94/GARP-targeted therapy applied to multiple vulnerable cancers will
overcome immune resistance to checkpoint inhibitors.
First, we will determine the roles and molecular mechanism involved in GRP94 regulation of TGFb biogenesis,
activation and signaling. This aim will focus on structural analysis of the GRP94-GARP complex, and on resolving
mechanisms of GRP94 in folding two other molecules important in regulating TGFb signaling: LRRC33 and
LRG1. Second, we will develop novel cancer immunotherapeutic strategies targeting GRP94 and GARP. The
goal is to advance the top first-in-class agent(s) among several pre-clinical leads through a milestone-driven
strategy. This includes agents to inhibit GARP cleavage, GARP-specific antibodies, drug-like GRP94-selective
inhibitors, antibodies against the cell surface GRP94 (ectoGRP94) preferentially expressed on cancer cells, and
T cells engineered to express chimeric antigen receptor (CAR) composed of a single-chain antibody against
ectoGRP94 fused with T cell signaling motifs (GRP94-CAR-T). Overall, the impact of this study lies in
fundamental understanding of GRP94 in regulating the TGFb pathway and in developing promising next
generation immunotherapeutic agents.

## Key facts

- **NIH application ID:** 10275810
- **Project number:** 1R01CA262069-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Zihai Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $569,160
- **Award type:** 1
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10275810

## Citation

> US National Institutes of Health, RePORTER application 10275810, Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy (1R01CA262069-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10275810. Licensed CC0.

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