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

阐明癌症信号通路如何促进维持免疫检查点阻断（immune checkpoint blockade, ICB）获得性或原发性耐药的免疫抑制程序，是提升免疫治疗疗效的关键步骤。在可影响ICB应答的通路中，干扰素（interferon, IFN）通路反而可能发挥有害而非有益的作用。本研究通过RNA-Seq、ATAC-Seq、流式细胞术及生化实验，检测了hMENA11a下调的生物学效应。经ICB治疗的患者肿瘤组织，通过搭载hMENA定制探针的Nanostring IO 360 Panel完成了基因表达谱分析。免疫传感器维甲酸诱导基因I（retinoic acid-inducible gene I, RIG-I）可诱导干扰素激活与分泌，其自身可被肌动蛋白细胞骨架紊乱所激活。肌动蛋白细胞骨架调控蛋白hMENA及其异构体是多种实体瘤中的关键信号枢纽，近期研究提示其可调控编码免疫调节分泌蛋白的基因转录。当肿瘤细胞表达hMENA且上皮特异性异构体hMENA11a水平较低时，可筛选出预后不良的非小细胞肺癌（non-small cell lung cancer, NSCLC）患者。本研究旨在鉴定由hMENA11a下调所调控的癌症内在与外在通路，以此作为NSCLC中ICB应答的决定因素。本文报道了一种由hMENA11a下调介导的ICB耐药新机制。