The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers

Abstract

Programmed cell death protein-1 (PD-1) is a checkpoint receptor expressed on the surface of various immune cells. PD-L1, the natural receptor for PD-1, is mainly expressed in tumor cells. Studies have indicated that PD-1 and PD-L1 are closely associated with the progression of human cancers and are promising biomarkers for cancer therapy. Moreover, the interaction of PD-1 and PD-L1 is one of the important mechanism by which human tumors generate immune escape. This article provides a review on the role of PD-L1/PD-1, mechanisms of immune response and resistance, as well as immune-related adverse events in the treatment of anti-PD-1/PD-L1 immunotherapy in human cancers. Moreover, we summarized a large number of clinical trials to successfully reveal that PD-1/PD-L1 Immune-checkpoint inhibitors have manifested promising therapeutic effects, which have been evaluated from different perspectives, including overall survival, objective effective rate and medium progression-free survival. Finally, we pointed out the current problems faced by PD-1/PD-L1 Immune-checkpoint inhibitors and its future prospects. Although PD-1/PD-L1 immune checkpoint inhibitors have been widely used in the treatment of human cancers, tough challenges still remain. Combination therapy and predictive models based on integrated biomarker determination theory may be the future directions for the application of PD-1/PD-L1 Immune-checkpoint inhibitors in treating human cancers.

Keywords: PD-1/PD-L1; biomarker; clinical application; human cancers; immunecheckpoint inhibitor.

Figure 1

Mechanisms of the response to anti-PD1/PD-L1 immunotherapy: PD-L1 is expressed in tumor cells and antigen presenting cells (APCs). PD-1 is mainly expressed in T cells, some tumor cells also express intrinsic PD-1. Immune escape occur after interaction of PD-1 and PD-L1. PD-1 can be phosphorylated by LCK to recruit tyrosine phosphatase Shp2, consequently inactivating CD28 and T cell receptor (TCR) function and signaling pathway, thus attenuating the activation signal of T cells and causing immune escape. Lck kinase activity is required to maintain PD-1/Shp2-mediated inhibitory signaling. The intervene of PD-1/PD-L1 immunocheckpoint inhibitors can effectively block the interaction between PD-L1 and PD-1, which in turn blocks the recruitment of SHP-2 and reactivates T cells signal for immune function.

Figure 2

Mechanisms of PD-1/PD-L1 inhibitors resistance: PD-1/PD-L1 inhibitor resistance is divided into primary resistance and acquired resistance. Mechanisms of primary resistance include lack of tumor immunogenicity; T-cell rejection; lack of interferon responsiveness, such as IFNγ (interferon Gamma) and IFNα (interferon alpha); EGFR (epidermal growth factor receptor) mutations and ALK (anaplastic lymphoma kinase) rearrangements; local immunosuppressive factors within the tumor microenvironment, such as MDSC (myeloid-derived suppressor cell) and TIM (tumor-infiltrating myeloid cell). While, the mechanisms of acquired resistance may be related to the following factors: exhaustion and loss of T cell function; impaired processing or presentation of neoantigens; complexity of the tumor microenvironment; mutations in associated genes, such as STK11/LKB1; dysbiosis of the gut microbiome; lack of Memory T Cells and upregulation of other Immune Checkpoints, such as CTLA-4(cytotoxic T-lymphocyte antigen-4), TIM-3(T cell immunoglobulin and mucin domain-containing molecule-3), LAG-3(lymphocyte activation gene-3) and VISTA(V-domain Ig suppressor of T cell activation).