# Immune Checkpoint Inhibitors as Antifibrotic Therapy for Idiopathic Pulmonary Fibrosis

> **NIH NIH K08** · STANFORD UNIVERSITY · 2020 · $167,292

## Abstract

Abstract
Idiopathic pulmonary fibrosis (IPF) is a deadly disease (50% of patients die within 3 years), and 
characterized by the onset of progressive scaring of the lung of yet unknown cause. There are no 
curative treatments other than lung transplantation and new treatment strategies are needed 
desperately. We recently published that c- JUN is a central molecular mediator of many fibrotic 
diseases (Wernig et al., PNAS 2017). We found that induction of c-Jun in mice was sufficient to 
induce severe fibrosis in the lung with features of lung fibrosis in humans. Single cell mass 
cytometry (CyTOF) in lung fibrosis revealed that c-Jun upregulates CD47, and our preliminary data 
demonstrate that it was also induced in human lung fibrosis. We subsequently could demonstrate that 
aCD47 antibody treatment reversed c-Jun-mediated fibrosis in the lung in our lung fibrosis mouse 
model.
Our preliminary CyTOF studies revealed that PD-L1, a second immune checkpoint protein was 
upregulated upon c-Jun induction, the ligand for the receptor PD1. Inhibiting the PD1/PD-L1 pathway 
has been recently shown to play an important role for tumor cell removal by tumor associated 
macrophages (Gordon et al., Nature 2017), however efficacy against IPF is yet unknown. Our 
preliminary data predict that blocking CD47 and PD-L1 could be highly effective in alleviating lung 
fibrosis in IPF. Last, we only have a sketchy understanding of the molecular mechanism underlying 
c-Jun induced fibrosis yet. Based on recently published work which demonstrated that transcription 
factors can directly regulate the expression of immune checkpoint proteins (Casey et al, Science 
2016), we hypothesize that CD47 and PD-L1 are direct genomic c-Jun targets. To test this 
hypothesis, we propose to perform Assay of Transposase Accessible Chromatin (ATAC)-Seq experiments 
in lung fibroblasts derived from primary IPF patient biopsies, which we receive through our 
collaborator Dr. Tushar Desai, head of the IPF Study Group at Stanford, with c-Jun gain and loss of 
function studies. We will subsequently confirm the ATAC-Seq data with orthogonal genomic assays.
Our proposed research will test efficacy of blocking the "don't see me (PD-L1)" and "don't eat me 
(CD47)" signals" in vivo as novel anti-fibrotic treatment for IPF and help understand the 
underlying molecular mechanism; if successful our findings have the potential to develop 
fundamentally new treatment approaches for IPF. By providing a rational basis for treatment of IPF 
with these novel immune therapies, our research will help pave the way for future clinical trials 
for patients with IPF. My multidisciplinary team of mentors and collaborators consisting of my 
primary mentor Dr. Irving Weissman and Drs. Tushar Desai, Howard Chang, and Garry Nolan, is 
comprised by expert leaders in immunology, lung biology, ATAC seq and CyTOF technologies and 
exceptionally positioned to provide all the support and guidance needed to test my three...

## Key facts

- **NIH application ID:** 9975880
- **Project number:** 5K08HL143143-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Gerlinde Wernig
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $167,292
- **Award type:** 5
- **Project period:** 2018-07-25 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975880

## Citation

> US National Institutes of Health, RePORTER application 9975880, Immune Checkpoint Inhibitors as Antifibrotic Therapy for Idiopathic Pulmonary Fibrosis (5K08HL143143-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9975880. Licensed CC0.

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