Radioproteomics stratifies molecular response to antifibrotic treatment in pulmonary fibrosis

Antifibrotic therapy with nintedanib is the clinical mainstay in the treatment of progressive fibrosing interstitial lung disease (ILD). High-dimensional medical image analysis, known as radiomics, provides quantitative insights into organ-scale pathophysiology, generating digital disease fingerprints. Here, we used an integrative analysis of radiomic and proteomic profiles (radioproteomics) to assess whether changes in radiomic signatures can stratify the degree of antifibrotic response to nintedanib in (experimental) fibrosing ILD. Unsupervised clustering of delta radiomic profiles revealed two distinct imaging phenotypes in mice treated with nintedanib, contrary to conventional densitometry readouts, which showed a more uniform response. Integrative analysis of delta radiomics and proteomics demonstrated that these phenotypes reflected different treatment response states, as further evidenced on transcriptional and cellular levels. Importantly, radioproteomics signatures paralleled disease- and drug related biological pathway activity with high specificity, including extracellular matrix (ECM) remodeling, cell cycle activity, wound healing, and metabolic activity. Evaluation of the preclinical molecular response-defining features, particularly those linked to ECM remodeling, in a cohort of nintedanib-treated fibrosing ILD patients, accurately stratified patients based on their extent of lung function decline. In conclusion, delta radiomics has great potential to serve as a non-invasive and readily accessible surrogate of molecular response phenotypes in fibrosing ILD. This could pave the way for personalized treatment strategies and improved patient outcomes. ### Competing Interest Statement D. Lauer has nothing to disclose. C.Y. Magnin has nothing to disclose. L. Kolly has nothing to disclose. H. Wang has nothing to disclose. B. Bunner has nothing to disclose. M. Chabria is cofounder of Tandem Therapeutics AG and holds share in the company. G.M. Cereghetti has nothing to disclose. H. Gabryś has nothing to disclose. S. Tanadini-Lang has nothing to disclose. A.C. Uldry has nothing to disclose. M. Heller has nothing to disclose. S. Verleden has nothing to disclose. K. Klein has nothing to disclose. A.C. Sarbu has nothing to disclose. M. Funke-Chambour has/had consultancy relationship with or speaker fees from Novartis, Boerhinger Ingelheim, GSK, MSD, Astra Zeneca, Pfizer, Sanofi. Has/had grant/research support from Boehringer Ingelheim, Roche. L. Ebner has nothing to disclose. O. Distler has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years): Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Beacon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience, and UCB. Patent issued 'mir-29 for the treatment of systemic sclerosis' (US8247389, EP2331143). B. Mauer has/had consultancy relationship with Novartis, Boehringer Ingelheim, Janssen-Cilag, GSK; grant/research support from AbbVie, Protagen, Novartis Biomedical; speaker fees from Boehringer-Ingelheim, GSK, Novartis; congress support from Medtalk, Pfizer, Roche, Actelion, Mepha, and MSD. Patent issued 'mir-29 for the treatment of systemic sclerosis' (US8247389, EP2331143). J. Gote-Schniering has nothing to disclose.