Combination therapy blocking TNF superfamily members 14 and 15 reverses pulmonary fibrosis.

Currently, anti-inflammatory drugs fail to reduce pulmonary fibrosis and tissue remodeling in the clinic. Thus, there is an unmet need to develop novel antifibrotic drugs capable of reversing disease. Our lab has identified two novel mediators of pulmonary fibrosis belonging to the tumor necrosis factor superfamily (TNFSF), LIGHT (TNFSF14) and TL1A (TNFSF15). Aside from their inflammatory roles, LIGHT and TL1A can directly activate structural cells involved in fibrosis, which express their receptors. Here, we show that LIGHT and TL1A receptors are both significantly elevated in patient pulmonary fibrosis biopsies as compared with healthy control lungs. Using gain-of-function studies, we found that LIGHT and TL1A can drive airway remodeling independently of one another. Furthermore, these TNFSF members synergize to maximize airway inflammation and fibrosis. We show that the combinatorial blockade of LIGHT and TL1A limits transforming growth factor β-driven profibrotic effects on fibroblasts in vitro. Moreover, LIGHT and TL1A stimulation of human epithelial cells and fibroblasts reveal distinct fibrotic signatures, including additive and synergistic profibrotic activities, in addition to some redundant profibrotic functions. Importantly, using antagonistic reagents neutralizing both LIGHT and TL1A signaling concomitantly post-disease onset in a bleomycin mouse model of pulmonary fibrosis, we observe a significant decrease in collagen deposition and smooth muscle accumulation as opposed to respective monotherapies blocking each molecule in isolation. This work highlights a therapeutic need to concomitantly target LIGHT and TL1A for treatment of pulmonary fibrosis disorders in humans.