CANNABIDIOL MODULATES CLASSICAL AND NON-CLASSICAL HLA EXPRESSION IN HUMAN CHORIOCARCINOMA CELL LINE

Abstract

Cannabidiol (CBD) modulates diverse signaling pathways with potential relevance to tumor immune escape, however its impact on the regulation of classical and non-classical HLA class I molecules remains incompletely understood. Here, we examined the mechanisms by which CBD regulates HLA expression in JEG-3 choriocarcinoma cells, focusing on cannabinoid-related receptors and intracellular Ca{superscript 2} signaling. CBD increased the expression of classical HLA class I genes--most notably HLA-C--while reducing HLA-G levels, a non-classical HLA class I molecule that acts as a local immunosuppressor. Receptor profiling revealed constitutive expression of CB1 and CB2, whereas GPR55 and PPAR{gamma} expression became detectable only after CBD exposure. Functional inhibition assays showed that HLA-G downregulation was selectively attenuated by CB1 blockade, with no meaningful contribution from CB2 or GPR55. In contrast, CBD-induced HLA-C upregulation required GPR55 and CB2 activity, while being unaffected by CB1 inhibition, indicating distinct receptor pathways for classical and non-classical HLA regulation. Calcium chelation using BAPTA further demonstrated that HLA-G modulation is highly sensitive to intracellular Ca{superscript 2} reduction, whereas classical HLA expression required higher BAPTA concentrations to be affected. Altogether, these findings identify CBD as a dual immunomodulatory agent capable of enhancing tumor immune visibility while limiting immunotolerant HLA-G expression through receptor-specific and Ca{superscript 2}-dependent mechanisms.