Journal Article

Prospects of the potential strategies to improve the efficacy of anti‐PD‐1/PD‐L1 therapy

Yamaguchi, Hirohito, Hung, Mien‐Chie, Wang, Shao‐Chun

2022

Overview

PD-L1 is highly glycosylated, and this post-translational modification is critical for PD-L1 protein stability and function.6,7 PD-L1 glycosylation is regulated by various oncogenic signalling pathways such as the epidermal growth factor receptor (EGFR) pathway, which inhibits phosphorylation of extracellular domain of PD-L1 by GSK3β.8 The phosphorylation by GSK3β hinders PD-L1 from its glycosylation, leading to its ubiquitin-mediated proteasome degradation.6 In addition, another study also indicates that glycosylation of PD-L1 interferes PD-L1 protein detection by some traditional PD-L1 antibodies that are designed to recognize its polypeptide antigens.9 Human cancer cell lines or tissues section of several cancer types treated with a glycosidase have the higher signals of PD-L1 in IHC staining than that of the untreated one, indicating that removal of N-linked glycosylation of PD-L1 enhances binding of traditional anti-PD-L1 mAb to PD-L1.9 Thus, it was proposed that inconsistent observations between PD-L1 IHC staining and clinical responses may be due to the failure of accurate PD-L1 detection in tumour tissues complicated by its glycosylation. [...]several studies have supported the notion that deglycosylation of tumour tissues improves predictive ability of PD-L1 expression in tumours as a marker for anti-PD-1/PD-L1 therapy.10–12 It is worth noting that in 2019, based on the IMpassion130 trial, the U.S. FDA granted accelerated approval to atezolizumab, a humanized anti-PD-L1 monoclonal antibody, in combination with nab-paclitaxel for treatment of advanced triple negative breast cancer (TNBC) patients, whose tumours show PD-L1 positivity by IHC tests from immune cells.13 However, in the following randomized Phase III clinical trial (IMpassion 131), the combination of atezolizumab and paclitaxel did not show significant clinical benefits compared to paclitaxel alone,14 and the atezolizumab TNBC indication was withdrawn voluntarily by Roche in 2021. [...]a larger cohort is warrant to develop further. [...]PD-L1 detection after deglycosylation by glycosidase pre-treatment may improve the predictive value of PD-L1 expression as a marker to select patients for ICI treatment (Figure 1).

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Antibodies / Biomarkers / Breast cancer / Clinical medicine / FDA approval / Immunotherapy / Ligands / Monoclonal antibodies / Phosphorylation / Response rates / Targeted cancer therapy / Tumors