# Targeting Fibroblast Discoidin Domain Receptor 2 for Immunotherapy to Pulmonary Fibrosis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $618,378

## Abstract

Progressive pulmonary fibrosis is a devastating condition that can lead to rapid death and current therapy is
only modestly effective. Tyrosine kinase inhibition with Nindedanib has proven to be a successful therapeutic
strategy for a number of pulmonary fibrosis disorders. However, due to the nonspecificity of Nintedanib it is
unclear which tyrosine kinases are most critical for driving fibrosis. Future mechanistic studies should focus on
identifying specific tyrosine kinases and cell types involved in fibrosis which may enable more precise targeting
of critical pro-fibrotic pathways. We have identified discoidin domain receptor 2 (DDR2) as an attractive
therapeutic target. DDR2 is a tyrosine kinase receptor activated by fibrillar collagens such as type I collagen
and we have recently shown that type I collagen signaling promotes further fibroblast activation leading to a
feed forward/postive feedback loop culminating in progressive fibrosis. Furthermore, unlike DDR1, which is
highly expressed by many cell types, DDR2 expression is heavily skewed with much higher expression on
fibroblasts than other cell types. This is critical because we have recently reported that activation of ubiquitous
intracellular signaling pathways can have opposing effects on fibrosis depending on the cell type with pro-
fibrotic activation within fibroblasts but anti-fibrotic effects within epithelial cells. Thus, DDR2 may enable more
specific targeting of fibroblasts which are the primary fibrogenic effector cells. Recently a novel DDR2-specific
inhibitor has been shown to improve outcome in a model of lung cancer through inhibition of cancer associated
fibroblasts and DDR2-expressing cancer cells which have undergone mesenchymal transition. In preliminary
data we find that this inhibitor is also effective at inhibiting fibrosis. Our preliminary data also support a novel
mechanism by which DDR2 signaling regulates PIK3C2α, a poorly understood member of the PI3 kinase
family which has recently been shown to regulate TGFβ receptor internalization necessary for TGFβ signaling.
PIK3Cα has also been shown to regulate PDK1/Akt signaling consistent with our report that DDR2 regulates
fibroblast survival through PDK1/Akt. Finally, a recent report found that targeting fibroblast specific markers
using a chimeric antigen receptor (CAR)-T cell approach was effective at attenuating cardiac fibrosis.
Collectively, this support our central hypothesis that DDR2 promotes fibrosis through fibroblast specific effects
on PIK3C2α/TGFβ signaling, resistance to apoptosis via PIK3C2α/PDK/Akt signaling and that DDR2
represents an attractive target for anti-fibrotic therapy. In addition to testing the importance of DDR2 with a
small molecule inhibitor, given skewed high fibroblast expression of DDR2, we will develop CAR-NK cells
targeting DDR2 for immunotherapy of pulmonary fibrosis. Unlike T cells, NK cells are not MHC restricted, do
not undergo clonal expansion and may therefore serve as of...

## Key facts

- **NIH application ID:** 10362183
- **Project number:** 1R01HL156998-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** KEVIN KEEWOUN KIM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $618,378
- **Award type:** 1
- **Project period:** 2021-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10362183

## Citation

> US National Institutes of Health, RePORTER application 10362183, Targeting Fibroblast Discoidin Domain Receptor 2 for Immunotherapy to Pulmonary Fibrosis (1R01HL156998-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10362183. Licensed CC0.

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