CD155 Cooperates with PD-1/PD-L1 to Promote Proliferation of Esophageal Squamous Cancer Cells via PI3K/Akt and MAPK Signaling Pathways

Simple Summary Some immunotherapies, such as anti-PD1 and anti-PD-L1 treatments, have been used to treat various tumors. However, they are less efficient against esophageal cancer, partially owing to a lack of research on the cellular and molecular mechanisms of this cancer. Therefore, various emerging immune checkpoints have been discovered in this post-PD-1 era. One such immune checkpoint is CD155, a protein belonging to the Nectin-like family and expressed on the surface of cancer and immune cells. Exploring the mechanisms and therapeutic applications of these immune checkpoints may effectively improve cellular responses to immunotherapies. In this study, we aimed to explore the role of CD155 in esophageal squamous cell cancer (ESCA) and its underlying molecular mechanism. CD155 was positively associated with PD-1/PD-L1 expression and could support ESCA proliferation. The downregulation of CD155 expression inhibited ESCA cell proliferation by impairing the cell cycle and inducing cell apoptosis. This occurred via the inhibition of PI3K/Akt and MAPK signaling pathways. In addition, Nectin3 may be the ligand of CD155 and may be involved in ESCA proliferation. Thus, our study suggests novel targets for tumor therapy, especially for ESCA treatment. Background: Esophageal cancer is still a leading cause of death among all tumors in males, with unsatisfactory responses to novel immunotherapies such as anti-PD-1 agents. Herein, we explored the role of CD155 in esophageal squamous cell cancer (ESCA) and its underlying molecular mechanisms. Methods: Publicly available datasets were used for differential gene expression and immune infiltration analyses, and their correlation with patient survival. A total of 322 ESCA and 161 paracancer samples were collected and evaluated by performing immunohistochemistry and the H score was obtained by performing semiquantitative analysis. In vitro transfection of ESCA cell lines with lentivirus vectors targeting CD155 was performed to knockdown the protein. These cells were analyzed by conducting RNA sequencing, and the effects of CD155 knockdown on cell cycle and apoptosis were verified with flow cytometry and Western blotting. In addition, in vivo experiments using these engineered cell lines were performed to determine the role of CD155 in tumor formation. A small interfering RNA-mediated knockdown of Nectin3 was used to determine whether it phenocopied the profile of CD155 knockdown. Results: CD155 is highly expressed in ESCA tissues and is positively associated with PD1, PDL1, CD4, IL2RA, and S100A9 expression. Furthermore, CD155 knockdown inhibited ESCA cells' proliferation by impairing the cell cycle and inducing cell apoptosis. Bioinformatics analysis of the gene expression profile of these engineered cells showed that CD155 mainly contributed to the regulation of PI3K/Akt and MAPK signals. The downregulation of Nectin3 expression phenocopied the profile of CD155 knockdown. Discussion: CD155 may cooperate with PD-1/PD-L1 to support ESCA proliferation in ways other than regulating its underlying immune mechanisms. Indeed, CD155 downregulation can impair ESCA cell pro-cancerous behavior via the inhibition of the PI3K/Akt and MAPK signaling pathways. Moreover, Nectin3 may be a ligand of CD155 and participate in the regulation of ESCA cells' proliferation. Hence, the inhibition of CD155 may enhance the therapeutic effect of anti-PD-1 immunotherapies in ESCA.