AKT-STAT3 Pathway as a Downstream Target of EGFR Signaling to Regulate PD-L1 Expression on NSCLC cells

Abstract

While cancer development and progression can be controlled by cytotoxic T cells, it is also known that tumor-specific CD8+T cells become functionally impaired by acquiring a group of inhibitory receptors known as immune checkpoints. Amongst those, programmed death-1 (PD-1) is one of the most recognized negative regulators of T cell function. In non-small lung cancers (NSCLCs), the aberrant activation of epidermal growth factor receptor (EGFR) is known to induce PD-L1 expression and further the treatment with gefitinib, a tyrosine kinase inhibitor (TKI) for EGFR, decrease the expression of PD-L1 on NSCLC. Given the acquired resistance to gefitinib treatment frequently observed by developing secondary-site mutations limiting its efficacy, it is important to understand the downstream mechanism of activated-EGFR signaling for regulating PD-L1 in NSCLC. In this study, we demonstrated that AKT-STAT3 pathway could be a potential target for regulating the surface expression of PD-L1 on NSCLCs with aberrant EGFR activity and, further, the inhibition of AKT or STAT3 activity could down-regulate the expression of PD-L1 even in gefitinib-resistant NSCLCs. These results highlight an importance of AKT-STAT3 pathway as a promising target for potentiating anti-tumor immune responses by regulating PD-L1 expression on cancer cells with aberrant EGFR activity.

IFN‐γ‐mediated inhibition of lung cancer correlates with PD‐L1 expression and is regulated by PI3K‐AKT signaling

“…In addition, we also found that IFN‐γ‐induced increased phosphorylation of STAT3. Activation of STAT3 as a downstream target of EGFR signaling regulated PD‐L1 expression . However, STAT3 as a downstream target of IFN‐γ does not affect IFN‐γ‐induced PD‐L1 expression in head and neck cancer .…”

A time for YAP1: Tumorigenesis, immunosuppression and targeted therapy

“…In bladder cancer, YAP1 expression is significantly associated with advanced clinicopathological stage and poor prognosis . YAP1 promotes bladder cancer cell growth and migration by cooperating with other molecules such as ANKRD17, KLF5, and COX2 …”

Targeting Sphingosine Kinases for the Treatment of Cancer

“…This postulate is based on the observations that PD-L1 expression in tumor cells is induced by IFN-γ (Cheng et al, 2007; Dondero et al, 2016; Iwai et al, 2002; Muhlbauer et al, 2006), and IFN-γ signaling is dependent on sphingolipid metabolism (Bajwa et al, 2017; Ottenlinger et al, 2016; Seo, Alexander, & Hahm, 2011; Wakita, Nishimura, Tokura, Furukawa, & Takigawa, 1996). Furthermore, Akt- (Abdelhamed, Ogura, Yokoyama, Saiki, & Hayakawa, 2016; Atefi et al, 2014; Dong et al, 2016; Lastwika et al, 2016; Song et al, 2013; Yang et al, 2017; Zhao et al, 2017), NF-kB- (Gowrishankar et al, 2015), and TNFα- (Wang et al, 2017) signaling induce PD-L1 expression, and all of these pathways are regulated by sphingolipid signaling. Therefore, manipulation of tumor immunology using SK inhibitors is an unexplored potential new approach to improved cancer therapy.…”