hMENA isoforms regulate cancer intrinsic Type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC [RNA-seq]

Understanding how cancer signaling pathways promote an immunosuppressive program which sustains acquired or primary resistance to immune checkpoint blockade (ICB) is a crucial step in improving immunotherapy efficacy. Among the pathways that can affect ICB response is the IFN pathway that may be detrimental rather than beneficial. Effects of hMENA11a down-regulation were tested by RNA-Seq, ATAC-Seq, flow cytometry and biochemical assays. ICB treated patient tumor tissues were profiled by Nanostring IO 360 Panel enriched with hMENA custom probes. The immune sensor retinoic acid-inducible gene I (RIG-I) induces IFN activation and secretion and is activated by actin cytoskeleton disturbance. The actin cytoskeleton regulatory protein hMENA, along with its isoforms, is a key signaling hub in different solid tumors, and recently its role as a regulator of transcription of genes encoding immunomodulatory secretory proteins has been proposed. When hMENA is expressed in tumor cells with low levels of the epithelial specific hMENA11a isoform, identifies NSCLC patients with poor prognosis. Aim was to identify cancer intrinsic and extrinsic pathways regulated by hMENA11a down-regulation as determinants of ICB response in NSCLC. Herein we present a novel mechanism of ICB resistance driven by hMENA11a down-regulation