Journal Article

Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker

Wu, Xiaoying, Wang, Zhengyi

2020

Overview

Immunocheckpoint proteins of tumor infiltrating lymphocytes play an important role in tumor prognosis in the course of tumor clinicopathology. PD‐1 (Programmed cell death protein 1) is an important immunosuppressive molecule. By binding to PD‐L1 (programmed cell death‐ligand 1), it blocks TCR and its costimulus signal transduction, inhibits the activation and proliferation of T cells, depletes the function of effector T cells, and enables tumor cells to achieve immune escape. In recent years, immunocheckpoint blocking therapy targeting the PD‐1/PD‐L1 axis has achieved good results in a variety of malignant tumors, pushing tumor immunotherapy to a new milestone, such as anti‐PD‐1 monoclonal antibody Nivolumab, Pembrolizumab, and anti‐PD‐L1 monoclonal antibody Atezolizumab, which are considered as potential antitumor drugs. It was found in clinical use that some patients obtained long‐term efficacy, but most of them developed drug resistance recurrence in the later stage. The high incidence of drug resistance (including primary and acquired drug resistance) still cannot be ignored, which limited its clinical application and became a new problem in this field. Due to tumor heterogeneity, current limited research shows that PD‐1 or PD‐L1 monoclonal antibody drug resistance may be related to the following factors: mutation of tumor antigen and antigen presentation process, multiple immune checkpoint interactions, immune microenvironment changes dynamically, activation of oncogenic pathways, gene mutation and epigenetic changes of key proteins in tumors, tumor competitive metabolism, and accumulation of metabolites, etc, mechanisms of resistance are complex. Therefore, it is the most urgent task to further elucidate the mechanism of immune checkpoint inhibitor resistance, discover multitumor universal biomarkers, and develop new target agents to improve the response rate of immunotherapy in patients. In this study, the mechanism of anti‐PD‐1/PD‐L1 drug resistance in tumors, the potential biomarkers for predicting PD‐1 acquired resistance, and the recent development of combination therapy were reviewed one by one. It is believed that, based on the complex mechanism of drug resistance, it is of no clinical significance to simply search for and regulate drug resistance targets, and it may even produce drug resistance again soon. It is speculated that according to the possible tumor characteristics, three types of treatment methods should be combined to change the tumor microenvironment ecology and eliminate various heterogeneous tumor subsets, so as to reduce tumor drug resistance and improve long‐term clinical efficacy. Based on the analysis of existing studies, ICB resistance involves complex network regulatory mechanisms, and the countermeasures against certain drug resistance mechanisms cannot solve the drawbacks of clinical drug resistance. In terms of treatment, traditional basic treatment, evidence‐based treatment of tumor type, and individual precision therapy should be integrated to comprehensively remove all subsets of cells in heterogeneous tumors.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Antibodies / Antigen presentation / Antigens / Antitumor activity / Apoptosis / Biomarkers / Cancer / Cancer Biology / Cell activation / Cell death / Cell proliferation / Cytotoxicity / Drug resistance / Effector cells / Epigenetics / Gene expression / Immune checkpoint inhibitors / immunocheckpoint blocker / Immunosuppressive agents / Immunotherapy / Lymphocytes / Lymphocytes T / mechanism / Medical prognosis / Metabolites / Monoclonal antibodies / Mutation / Patients / PD-1 protein / PD-L1 protein / PD‐1/PD‐L1 / Pembrolizumab / Phosphatase / Point mutation / Proteins / resistance / Review / Signal transduction / study and analysis / T cell receptors / Targeted cancer therapy / Tumor cells / Tumors