A novel kinase inhibitor ax-0085 inhibits interferon-γ-mediated induction of pd-l1 expression and promotes immune reaction to lung adenocarcinoma cells

Jusong Kim, Haeyeon Jang, Gyu Jin Lee, Yelim Hur, Juhee Keum, Jung Ki Jo, Si Eun Yun, Sung Jun Park, Young Jun Park, Myeong Jun Choi, Kye Seong Kim, Jaesang Kim

Research output: Contribution to journalArticlepeer-review

Abstract

In this study, we describe a novel kinase inhibitor AX-0085 which can suppress the induction of PD-L1 expression by Interferon-γ (IFN-γ) in lung adenocarcinoma (LUAD) cells. AX-0085 effectively blocks JAK2/STAT1 signaling initiated by IFN-γ treatment and prevents nuclear localization of STAT1. Importantly, we demonstrate that AX-0085 reverses the IFN-γ-mediated repression of T cell activation in vitro and enhances the anti-tumor activity of anti-PD-1 antibody in vivo when used in combination. Finally, transcriptomic analyses indicated that AX-0085 is highly specific in targeting the IFN-γ-pathway, thereby raising the possibility of applying this reagent in combination therapy with checkpoint inhibitor antibodies. It may be particularly relevant in cases in which PD-L1-mediated T cell exhaustion leads to immunoevasive phenotypes.

Original languageEnglish
Article number19
JournalCells
Volume11
Issue number1
DOIs
StatePublished - 2022 Jan 1
Externally publishedYes

Keywords

  • AX-0085
  • Cancer immunotherapy
  • Immune checkpoint
  • Lung adenocarcinoma
  • PD-L1

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