Synthetic RIG-I agonist-mediated cancer immunotherapy synergizes with MAP-Kinase inhibition against BRAF mutated melanoma [YUMM1.7]

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: YUMM1.7 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.