Resistance Mechanisms to Programmed Cell Death Protein 1 and Programmed Death Ligand 1 inhibitors.

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.