Beyond PD-L1/PD-1: expression of PVR/TIGIT and TNFRSF14/BTLA axes in response to Helicobacter pylori and in gastric cancer lesions.

Gastric cancer (GC) has a high mortality rate worldwide, mainly due to late detection and lack of effective treatments. Immune checkpoint (ICs) inhibitors have revolutionized cancer treatment; however, a substantial percentage of patients with GC do not respond to this treatment, which may be related to aspects underlying the conformation of the immune microenvironment during tumor development and progression. In this study, we assessed the role of Helicobacter pylori, the most recognized GC risk factor, in the concomitant induction of PD-L1, B7-H3, PVR, TNFRSF14, Gal-3, and Gal-9 in vitro. We also analyzed the expression of selected IC ligand-receptor axes in human GC lesions. The mRNA relative expression of PD-L1, PVR, and TNFRSF14 was significantly upregulated in human cell lines challenged with the bacterium. This was CagPAI dependent and further enhanced by PBMCs. In GC lesions, mRNA levels in the PVR/TIGIT and TNFRSF14/BTLA axes were higher than in the PD-L1/PD-1 axis. When the protein levels of these ICs axes were determined by flow cytometry on the different cell subpopulations of the tumor microenvironment, Tregs emerged as the lymphoid subpopulation contributing the most to the expression of PD-1, TIGIT, and BTLA receptors; their ligands were mainly expressed by GC cells. Our results suggest that, in addition to the PD-L1/PD-1 axis, PVR/TIGIT and TNFRSF14/BTLA axes may play a role in establishing an immunosuppressive microenvironment during GC development and progression. This study also highlights the potential relevance of Tregs as active players in shaping and maintaining an immunosuppressive milieu in GC lesions, in part through expression of ICs.