Resistance Mechanisms to Programmed Cell Death Protein 1 and Programmed Death Ligand 1 Inhibitors Publisher Pubmed



Pezeshki PS^{1, 2} ; Mahdavi Sharif P^{1, 2} ; Rezaei N^{3, 4, 5} Show Affiliations
Source: Expert Opinion on Biological Therapy Published:2021

Abstract

Introduction: In the past few years, administrating monoclonal humanized antibodies, namely checkpoint inhibitors, against programmed cell death protein 1 (PD-1), and its ligand (PD-L1), has yielded reassuring tumor regression rates. Anti-PD-1/PD-L1 checkpoint inhibitors disrupt the engagement of PD-1 on T-cells and their ligands on tumor or other target cells and reactivate the tumor-specific T infiltrating lymphocytes (TILs), which are mostly in a state of anergy before the PD-1/PD-L1 blockade. However, a limited number of patients initially respond, and the others show a primary (innate) resistance. Moreover, the rate of relapse and tumor progression after a partial, or even complete response (secondary or acquired resistance) is relatively considerable. Areas covered: This paper presents a comprehensive discussion on the mechanisms of primary and secondary resistance to PD-1/PD-L1 blockade. Loss of T-cell infiltration or T-cell exclusion, lack of PD-L1 or PD-1 expression, and also lack of tumor immunogenicity are among the most important mechanisms, and also biomarkers of resistance in patients undergoing PD-1/PD-L1 blockade. Several somatic mutations in tumors are known to be related to at least one of the resistance mechanisms. Expert opinion: Identification of the novel resistance mechanisms suggests further combinatorial therapies to tackle primary and secondary resistance to PD-1/PD-L1 blockade. © 2021 Informa UK Limited, trading as Taylor & Francis Group.