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.
Highlights
Cancer immunotherapy, in particular via immune checkpoint inhibition, currently represents the most promising therapeutic intervention against multiple types of cancer, including lung cancer, one of the top-ranked cancers in incidence as well as in mortality [1–4]
The interaction between PD-L1 and PD-1 expressed, respectively, in tumor cells and in immune cells constitutes the essence of immune checkpoint blockade response [3]
We examined the effect of IFN-γ treatment on PD-L1 expression in lung adenocarcinoma (LUAD) cells
Summary
In particular via immune checkpoint inhibition, currently represents the most promising therapeutic intervention against multiple types of cancer, including lung cancer, one of the top-ranked cancers in incidence as well as in mortality [1–4]. Identifying the diverse factors that affect the immune-evasive behaviors of tumor cells and predicting the ultimate outcome of a given immunotherapy are major topics of current investigations. An important interaction between immune cells and tumor cells is mediated by IFN-γ-signaling [13]. This pleiotropic cytokine has been known to act in both ‘anti-tumor’ and ‘pro-tumor’ manners, depending on the types of cancer and contexts of interaction with immune cells [13]. The interaction between the two molecules induces T cell exhaustion and inhibits T cell activation required for effective targeting of tumor cells [14–16]. We provide evidence in vitro and in vivo that AX0085 represents a potential therapeutic reagent that can enhance the anti-tumor efficacy of antibody treatments
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