Description

Combination of targeting RIG-I with inhibition of the PD1-PDL1 axis leads to synergistic immunotherapeutic efficacy in a model of hepatocellular carcinoma

L. Posselt, P. Duewell, D. Mayr, S. Endres, S. Rothenfusser, M. Schnurr, L. M. Koenig

Klinikum der Universität München, Germany

Hepatocellular carcinoma (HCC) is one of the most aggressive tumors in the world with a very poor 5-year survival rate of approximately 5-6%. Immunotherapeutic treatment of HCC using immune checkpoint inhibitors has generated very promising but moderate results in clinical trials and has to be further evaluated. We and others have demonstrated that the cytosolic helicase RIG-I senses viral 5’-triphosphate-RNA (ppp-RNA) and induces type I IFN-driven immune responses that combat both viral infections as well as tumors. Here, we identify RIG-I as a potent immunotherapeutic target in HCC evaluate the combination of RIG-I activation and immune checkpoint inhibition to increase treatment efficacy.

To measure the expression and function of RIG-I in HCC we analyzed human IHC tumour samples and human and mouse murine HCC cell lines. Therapeutic efficacy was evaluated in vitro and in vivo in an orthotopic HCC mouse model. Immune cell depletion and knock out mouse lines were used to decipher the mechanism of the antitumoral immune response.

Transfection of human and murine HCC cells with ppp-RNA induced phosphorylation of IRF-3, production of IFN-b and CXCL10 and induction of profound tumor cell death. Treatment of mice with orthotopic HCC with ppp-RNA lead to systemic and intratumoral type I IFN production and significantly prolonged survival in a CD8⁺-T cell-dependent manner while anti-PD1 antibody treatment did not significantly alter the overall survival. In combination, both treatments synergistically augmented therapy efficacy leading to a significantly prolonged survival.

In conclusion, RIG-I is a promising target for HCC therapy and the combination of immunostimulation via Rig-I ligands with the blockage of immunoinhibition via anti-PD1 antibody treatment shows encouraging results for the treatment of HCC and possibly other tumour entities.

Funding: DFG