PD1 / PDCD1 / CD279, a type 1 transmembrane protein of the Ig superfamily, consists of an extracellular N-terminal IgV-like domain, a transmembrane domain, and a cytoplasmic tail engaging in inhibitory signal transmission. Being expressed on activated immune cell types including T cells, B cells, natural killer (NK) cells, NKT cells, dendritic cells (DCs), macrophages, and host tissues, the expression on effector T cells is associated with constitutive antigen exposure and thus PD1 / PDCD1 / CD279 has become a marker of T cell unresponsiveness or exhaustion.
PD1 / PDCD1 / CD279 has two known ligands, PD-L1 / B7-H1 / CD274 and PD-L2 / B7-DC / CD273, which belong to B7 family. PD-L1 / B7-H1 / CD274 is the major ligand and expressed on hematopoietic cells including T cells, B cells, DCs, macrophages and mast cells as well as many nonhematopoietic cells including endothelial cells and numerous epithelial cells. PD-L1 / B7-H1 / CD274 is expressed on many tumors including cancers developing in various organs such as head and neck, lung, stomach, colon, pancreas, breast, kidney, bladder, ovary, cervix, as well as melanoma, glioblastoma, multiple myeloma, lymphoma, and various leukemias, thereby inhibits effective anti-tumor immune responses mediated by PD1 / PDCD1 / CD279 -expressed T cells.
(1) PD1 / PDCD1 / CD279 and PD-L1 / B7-H1 / CD274 interact with each other and then inhibit expression of multiple transcription factors of T cells such as GATA-3 and T-bet. Besides, the PD1 & PD-L1 immune checkpoint pathway inhibits the proliferation, survival, and effector function of CD8+ cytotoxic T lymphocyte (CTL) and thus induces apoptosis of tumor-infiltrating T cells. Ectopic PD-L1 / B7-H1 / CD274 expression in tumor cells in a syngeneic transplant model facilitated the escape of the tumor cells from CTL control. (2) Besides, it was shown that PD-L1 expression plays a critical role in differentiation of regulatory T cells (Tregs) and maintaining their suppressive function. Because Tregs are important inhibitors of tumor-specific immune responses in the tumor microenvironment, PD1 & PD-L1 immune checkpoint pathway-mediated generation of Tregs can help as another layer of protection to immune evasion of tumors. Therefore, blockage of PD1 / PDCD1 / CD279 or PD-L1 / B7-H1 / CD274 can activate the anti-tumor activity through both effector T cell activation and Treg inhibition. (3) Additionally, PD1 & PD-L1 immune checkpoint pathway can promote the differentiation of CD4+ T cells into FOXP3+ Tregs, further suppressing the immune system and resulting in peripheral immune tolerance in cancer patients. (4) As well, the effects of PD1 / PDCD1 / CD279 blockade can be mediated partially by B cells or NK cells. An in vitro study revealed that PD1 / PDCD1 / CD279 could inhibit stimulating signals of B cell receptors, leading to restoration of B cell activation after transfecting gene fragments of PD1 / PDCD1 / CD279 into B lymphoma cell lines. It has been reported that B cell antigen receptor signal inhibits B cell proliferation and function by inducing PD1 / PDCD1 / CD279 expression and Tumor-produced IL-18 inhibits the function of NK cells via enhancing PD1 / PDCD1 / CD279 expression.
Kathleen M. et al. The NextImmune-CheckpointInhibitors:PD-1/PD-L1 Blockade in Melanoma. Clinical Therapeutics. 2015; 37:4
Mei Ji et al. PD-1/PD-L1 pathway in non-small-cell lung cancer and its relation with EGFR mutation. Journal of Translational Medicine (2015) 13:5