The Immunoglobulin Superfamily Receptome Defines Cancer-Relevant Networks Associated with Response to Immunotherapy

Abstract

Abstract Background Cell surface receptors fundamentally determine physiological and pathological signaling, and as such, deciphering the ensemble of receptor-ligand interactions in the extracellular milieu is vital to understand cellular communication and identify new therapeutic targets. Despite its clinical relevance, the Immunoglobulin Superfamily (IgSF) remains remarkably uncharacterized and many proteins, including some immune checkpoints, are orphan. In this study, we present the first experimentally validated map of receptor-ligand interactions, the IgSF Interactome. Methods An automated platform for unbiased and high sensitivity receptor discovery was implemented. Using this technology, we interrogate 445 IgSF proteins for binding to most single transmembrane receptors in the human genome. Results The IgSF Interactome consists of over 500 interactions, with 85% previously unreported. Using orthogonal methodologies, we confirm loss-of-binding mutations specifically found in tumors, as well as new potential modulators for immune checkpoints such as PD-L1/PD-L2. Integration of this map of extracellular interactions with gene expression profiles in tumors and healthy tissues reveals receptor-ligand networks dysregulated in cancer. Furthermore, investigation of the IgSF Interactome in a large cohort of patients with metastatic urothelial cancer who were treated with the anti-PD-L1 agent Atezolizumab identifies interacting protein signatures associated with clinical outcome, suggesting new determinants of response to treatment. Conclusion The IgSF Interactome represents the first map of receptor-ligand interactions in humans, providing a framework for understanding the functional organization of the surfaceome during homeostasis and disease, and ultimately informing therapeutic development. Legal entity responsible for the study Genentech, Inc. Funding Genentech, Inc. Disclosure N. Martinez-Martin: Shareholder / Stockholder / Stock options: Roche. E. Verschueren: Shareholder / Stockholder / Stock options: Roche. B. Husain: Shareholder / Stockholder / Stock options: Roche.