TY - JOUR T1 - Comprehensive analyses of immunodynamics and immunoreactivity in response to treatment in <em>ALK</em>-positive non-small-cell lung cancer JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1136/jitc-2020-000970 VL - 8 IS - 2 SP - e000970 AU - Kyoung-Ho Pyo AU - Sun Min Lim AU - Chae-Won Park AU - Ha-Ni Jo AU - Jae Hwan Kim AU - Mi-Ran Yun AU - Dohee Kim AU - Chun-Feng Xin AU - Wongeun Lee AU - Bianca Gheorghiu AU - Min Hee Hong AU - Hye Ryun Kim AU - Hyo Sup Shim AU - Mi Jang AU - Sung Sook Lee AU - Byoung Chul Cho Y1 - 2020/07/01 UR - http://jitc.bmj.com/content/8/2/e000970.abstract N2 - Background EML4-ALK is a distinct molecular entity that is highly sensitive to ALK tyrosine kinase inhibitors (TKIs). Immune checkpoint inhibitors (ICIs) have not proved efficacy in ALK-positive non-small cell lung cancer so far. In this study, we performed a mouse clinical trial using EML4-ALK transgenic mice model to comprehensively investigate immunomodulatory effects of ALK TKI and to investigate the mechanisms of resistance to ICIs.Methods EML4-ALK transgenic mice were randomized to three treatment arms (arm A: antiprogrammed death cell protein-1 (PD-1), arm B: ceritinib, arm C: anti-PD-1 and ceritinib), and tumor response was evaluated using MRI. Progression-free survival and overall survival were measured to compare the efficacy. Flow cytometry, multispectral imaging, whole exome sequencing and RNA sequencing were performed from tumors obtained before and after drug resistance.Results Mouse clinical trial revealed that anti-PD-1 therapy was ineffective, and the efficacy of ceritinib and anti-PD-1 combination was not more effective than ceritinib alone in the first line. Dynamic changes in immune cells and cytokines were observed following each treatment, while changes in T lymphocytes were not prominent. A closer look at the tumor immune microenvironment before and after ceritinib resistance revealed increased regulatory T cells and programmed death-ligand 1 (PD-L1)-expressing cells both in the tumor and the stroma. Despite the increase of PD-L1 expression, these findings were not accompanied by increased effector T cells which mediate antitumor immune responses.Conclusions ALK-positive tumors progressing on ceritinib is not immunogenic enough to respond to immune checkpoint inhibitors. ER -