Synergistic effects of cannabidiol and cytokine-induced killer cells via the modulation of TRPV2 channel and intracellular p-ERK 1/2 expression on non-small cell lung cancer cells

Abstract A multitude of findings from the cell cultures and animal studies are available to support the anti-cancer properties of cannabinoids cannabidiol (CBD). Since CBD acts on multiple molecular targets, its clinical adaptation, especially in combination with cancer immunotherapy regimen remains a serious concern. Considering this, herein, we extensively studied the effect of CBD on the cytokine-induced killer (CIK) cells immunotherapy approach using multiple non-small cell lung cancer (NSCLC) cells harboring diverse genotypes. Our analysis showed that, a) CB2 receptor surface and intracellular expression increased significantly in NSCLC cells following co-culture with CIK cells, b) CBD exerts a pronounced synergistic effect on CIK-mediated lysis, resulting in a substantial increase in IFN-γ production, c) CBD explicitly promotes the CD25+CD69+ population and CD62L−CD45RA+ terminal effector memory (EMRA) population in NKT-CIK cells, suggesting an activation and effector memory T-cell differentiation. Of interest, we observed that clinically relevant CBD concentrations enhanced the calcium influx (mediated by the TRPV2 channel) and p-ERK expression directly in CIK cells, while in cancer cells it induced DNA double-strand breaks via upregulation of histone H2AX phosphorylation. Notably, the migration and invasion ability of NSCLC cells suppressed by CBD (in the absence of CIK cells) was rescued using the TRPV2 antagonist (Tranilast). We further investigated the epigenetic effects of this synergy and found that combining CBD with CIK cells decreased the LINE-1 mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation. Taken together, CBD holds a great potential for treating NSCLC with CIK cell immunotherapy and its complete success requires careful consideration of the patients' genetic background.