The Molecular Function And Mechanism Of Tumor Cell-Intrinsic PD-1 In Cancer

Programmed cell death protein 1(PD-1)is a type ? transmembrane glycoprotein,which is a negative regulator of immune response.PD-1 inhibits the activation of T lymphocytes by binding to its two ligands,PD-1 ligand 1(PD-L1)and PD-1 ligand 2(PD-L2).PD-L1 is also expressed in tumor cells and is involved in tumor immune escaping.Antibodies targeting PD-1 and PD-L1 are able to block the interaction between PD-1 on the surface of T cells and PD-L1 on the surface of tumor cells,so that T cells are activated and kill the tumor cells.PD-1 and PD-L1-targeted antibodies have been used to treat a variety of human tumors,including melanoma,renal cell carcinoma,non-small cell lung cancer(NSCLC),Hodgkin's lymphoma.However,it has been found that PD-1 is expressed in certain tumor cells,such as melanoma and hepatocellular carcinoma in recent years.In this study,I explored the expression of PD-1 and the potential molecular function and mechanism in tumor cells.First,I found that a subpopulation of tumor cells expresses both PD-1 and PD-L1.Second,I constructed PD-1 or PD-L1 knockdown and overexpression cell lines,and found that the silencing of PD-1 or PD-L1 promotes cell proliferation and colony formation in vitro and tumor growth in vivo.Conversely,overexpression of PD-1 or PD-L1 inhibits tumor cell proliferation and colony formation.These data indicate that PD-1/PD-L1 is a potential tumor suppressor.Then,we treated tumor cells with antibodies targeting PD-1 or PD-L1,including Nivolumab,Pembrolizumab,and Atezolizumab,and found that these antibodies targeting PD-1 or PD-L1 promote tumor growth in cell cultures and xenografts.Mechanistically,we found that the coordination of PD-1 and PD-L1 in tumor cells affects cell proliferation through two major signaling pathways including AKT and ERK1/2 signaling pathways.This study demonstrates that PD-1/PD-L1 is a potential tumor suppressor and potentially regulates the response to anti-PD-1/PD-L1 treatments,thus representing a potential biomarker for the optimal cancer immunotherapeutic treatment.