Pivotal role of PD-1/PD-L1 as an immune checkpoint in lymphoma and solid tumor: Cellular organization, clinical implications & the potential of small molecule inhibitors.

Cancer immunotherapy has been a paradigm shift for treatment of advanced malignancies. Small-molecule inhibitors offer inherent advantages in terms of pharmacokinetics and drug ability, thereby providing an opportunity for cancer treatment and achieving better therapeutic effects. Immune checkpoint inhibitors (ICI) constitute a novel mechanism for the killing, and block evasion of the tumor cells leading to long lasting immune response, and offers promising advancement in clinical medicine. Programmed cell death protein 1 receptor and its ligand (PD-1/PD-L1) have demonstrated remarkable immune modulation. Antibodies against PD-1 or PD-L1 have shown significant promise although stability and immunogenicity issues pose critical disadvantages. In this review, we will discuss how PD-1/PD-L1 modulates the immune cells and tumor cells in the tumor microenvironment following immunotherapy. We will also discuss how the immunomodulatory potential of these inhibitors can be exploited via rational combinations with targeted therapy including immunotherapy and chemotherapy. Besides that, the current clinical and preclinical results of PD-1/PD-L1 will be highlighted in cancer including lymphoma in response to the host immune system. We will also summarize the pharmacokinetics and pharmacodynamics of this small molecule inhibitor including the significant role of nanoparticle (NP) controlled drug delivery system (DDS) using current data from clinical and pre-clinical trials on mono and combination immunotherapy to overcome therapeutic limitations of ICI. Combining the NP mediated DDS with ICI therapy could provide a profitable immunotherapeutic strategy for cancer treatment.