RT Journal Article SR Electronic T1 Comprehensive analyses of immunodynamics and immunoreactivity in response to treatment in ALK-positive non-small-cell lung cancer JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP e000970 DO 10.1136/jitc-2020-000970 VO 8 IS 2 A1 Kyoung-Ho Pyo A1 Sun Min Lim A1 Chae-Won Park A1 Ha-Ni Jo A1 Jae Hwan Kim A1 Mi-Ran Yun A1 Dohee Kim A1 Chun-Feng Xin A1 Wongeun Lee A1 Bianca Gheorghiu A1 Min Hee Hong A1 Hye Ryun Kim A1 Hyo Sup Shim A1 Mi Jang A1 Sung Sook Lee A1 Byoung Chul Cho YR 2020 UL http://jitc.bmj.com/content/8/2/e000970.abstract AB 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.