Synthetic RIG-I agonist-mediated cancer immunotherapy synergizes with MAP-Kinase inhibition against BRAF mutated melanoma

The implementations of targeted molecular therapies and immunotherapy in melanoma vastly improved the therapeutic outcome in patients with limited efficacy of surgical intervention. Nevertheless, a large fraction of melanoma patients still remains refractory or acquires resistance to these new forms of treatment, illustrating a need for improvement. Here we report that the clinically relevant combination of MAP kinase inhibitors Dabrafenib and Trametinib synergizes with RIG-I agonist-induced immunotherapy to kill BRAF-mutated human and mouse melanoma cells. Kinase inhibition did not compromise the agonist-induced innate immune response of the RIG-I pathway in host immune cells. In a melanoma transplantation mouse model, the triple therapy outperformed the individual therapies. Our study suggests that targeted activation of RIG-I with its synthetic ligand 3pRNA could vastly improve tumor control in a substantial fraction of melanoma patients receiving MAP kinase inhibitors. Overall design: A375 cells were treated for 24 hours with DMSO, Dabrafenib, Trametinib or the combination of both. Additionally, each condition was left unstimulated, transfected with CA21 control RNA or the activating RIG-I ligand 3pRNA. Total RNA was isolated and subjected to poly-A based library preparation.