Comprehensive analyses of immunodynamics and immunoreactivity in response to treatment in ALK-positive non-small-cell lung cancer

Kyoung Ho Pyo, Sun Min Lim, Chae Won Park, Ha Ni Jo, Jae Hwan Kim, Mi Ran Yun, Dohee Kim, Chun Feng Xin, Wongeun Lee, Bianca Gheorghiu, Min Hee Hong, Hye Ryun Kim, Hyo Sup Shim, Mi Jang, Sung Sook Lee, Byoung Chul Cho

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2 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalJournal for ImmunoTherapy of Cancer
Volume8
Issue number2
DOIs
Publication statusPublished - 2020 Jul 1

Bibliographical note

Publisher Copyright:
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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