Novel immunotherapeutic approaches to cancer: Voltage-gated sodium channel expression in immune cells and tumors

Abstract Although “immunotherapy” is a wonderful concept causing major excitement in cancer clinics and giving much hope to patients, significant limitations remain in its applications. Consequently, there is unmet need to improve the existing immunotherapies as well as to develop novel strategies. In both regards, ion channels and transporters expressed widely in cells of the immune system as well as cancer cells offer significant potential. Here, we focus on voltage-gated sodium channels (VGSCs). Expression of VGSCs (Nav1.5) occurs in immature thymocytes and controls positive selection of CD4+ lymphocytes. Motility of T-lymphocytes and macrophages is promoted by VGSC activity. In contrast, in natural killer (NK) cells, VGSCs dampen the cells’ cytotoxic potential. Several cancers express the neonatal splice variant of Nav1.5 and this raises several possible ways in which it can be incorporated into immunotherapy. Possibilities include chimeric antigen receptor (CAR)-T or CAR-NK cell therapies and vaccines. Independently, importantly, it is well known that VGSC blockers can serve as antimetastatic drugs. Thus, “combination therapies” involving co-application of VGSC blockers with checkpoint inhibitors or vaccines are also conceivable. Indeed, checkpoint inhibition has been shown to depend on tumors’ status of epithelial-mesenchymal transition, which is controlled in part by VGSC activity. Finally, there is evidence showing that ionic activity associated with VGSC activity (e.g., pH regulation) can also modulate the effectiveness of immunotherapy. While many questions remain, and some of these are highlighted, we conclude that VGSC expression offers significant clinical potential (alone or in combination) in immunotherapeutic approaches to cancer.