Bispecific Targeting of CHI3L1 and PD-1/PD-L1 Axis as a Novel Therapeutic Strategy for Idiopathic Pulmonary Fibrosis
Abstract
Pulmonary fibrosis is a devastating lung disease that affects up to 200,000 individuals in the United States alone and 5 million worldwide. Idiopathic Pulmonary Fibrosis (IPF) is the most common form of pulmonary fibrosis and has poor prognosis, with median survival only 2 to 3 years following diagnosis. IPF disproportionately affects men, older individuals, and is associated with cigarette smoking and combat-related particulate exposures. Thus, pulmonary fibrosis is a critical health issue for both civilians and Veterans. Currently, two U.S. Food and Drug Administration (FDA)-approved drugs, nintedanib and pirfenidone, are available for patients with IPF; however, these drugs only provide limited benefits and do not cure or reverse disease progression. Therefore, new drugs, methods of prevention or treatment of pulmonary fibrosis based on new pathogenetic mechanisms are critically necessary. Recent studies using unbiased single cell RNAseq analysis on fibrotic lungs from IPF patients revealed that a specific subtype of lung macrophages is implicated in the pathogenesis of IPF. These studies also demonstrated that Chitinase 3-like 1 (CHI3L1; also called YKL-40 in man), the prototypic CLP, is highly expressed in profibrotic macrophages. It is also reported that CHI3L1 regulates the invasive phenotypes of fibroblasts that play an important role in certain tumor invasion and metastatic processes. These studies suggest that CHI3L1 plays a significant role in the development and progression of pulmonary fibrosis. However, the cellular and molecular mechanisms that CHI3L1 uses to regulate fibrotic tissue response have not yet been clearly understood. There are several pieces of evidence that supports the claim that CHI3L1 plays an important role in the development of profibrotic macrophages and invasive fibroblasts: (1) profibrotic macrophages that express high levels of CHI3L1 distinctly overlap with macrophage populations found in IPF patients but not in other lung diseases in multiple patient cohorts; (2) CHI3L1 drives PD-L1 expression, PD-L1 being the characteristic marker required for invasive fibroblasts; and (3) CD44, a putative receptor for CHI3Ll, mediates invasive phenotypes of fibroblasts. These studies suggest that CHI3L1 could be a major driver of these profibrotic cellular compartments leading to progressive and severe pulmonary fibrosis. It is also reasonable to speculate that the excessive accumulation of extracellular matrix seen in IPF patients is rest from an unchecked positive feedback loop between these cellular compartments. These studies led us to think that simultaneously targeting these profibrotic cellular compartments-consisting of profibrotic macrophages and invasive fibroblasts, deemed the macrophage fibroblast trophic unit, could be a way to block or reverse ongoing pulmonary fibrosis. In this sense, the CHI3L1 and PD-1/PD-L1 axes could be a reasonable therapeutic target to block the development or activation of these profibrotic cells. Preliminary studies targeting the CHI3L1 or PD-1/PD-L1 axes through neutralizing monoclonal antibodies significantly suppress bleomycin-induced pulmonary fibrosis. Surprisingly, simultaneous targeting of the CHI3L1 and PD-1/PD-L1 axes showed the most prominent antifibrotic effects compared to anti-CHI3L1 or anti-PD1 antibody only treatments, suggesting additive or synergistic interactions between CHI3L1 and PD-1/PD-L1 axes. These studies led to the hypothesis that bispecific targeting of CHI3L1 and PD-1/PD-L1 axes is a novel and effective therapeutic strategy to block or reverse both profibrotic macrophage and invasive fibroblast activation in pulmonary fibrosis. This project aims to gain a better mechanistic understanding of CHI3L1 in this process and evaluate the therapeutic efficacy of bispecifically targeting the CHI3L1 and PD-1/PD-L1 axes. To achieve this, the role and effect of CHI3L1 in the development of profibrotic macrophages and invasive fibroblasts ex
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210041
Entities
People
- Chun Geun Lee
Organizations
- Brown University
- United States Army