(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 Next Immune-Checkpoint Inhibitors:PD-1/PD-L1 Blockade in Melanoma. Clinical Therapeutics. 2015; 37:4