Lnc-CCNH-8 promotes immune escape by up-regulating PD-L1 in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a common malignancy with poor prognosis. In recent years, immune checkpoint inhibitors (ICI) have made breakthroughs in the clinical treatment of HCC, but the overall response rate to ICI in HCC patients is still low, and no validated biomarker is available to guide clinical decision making. Here, we demonstrated that long non-coding RNA Lnc-CCNH-8 is highly expressed in HCC and correlates with poor prognosis. Functionally, elevated Lnc-CCNH-8 inactivated cocultured T cells in vitro and compromised antitumor immunity in an immunocompetent mouse model. Mechanistically, upregulated Lnc-CCNH-8 can sponge miR-217 to regulate the expression of PD-L1. In addition, Lnc-CCNH-8 can also stabilize PD-L1 through miR-3173/PKP3 axis. Furthermore, mice bearing tumors with high lnc-CCNH-8 expression had significant therapeutic sensitivity to anti-PD-L1 monoclonal antibody treatment. More importantly, HCC patients with high level of plasma exosomal Lnc-CCNH-8 had a better therapeutic response to ICI. Taken together, our results reveal the function of Lnc-CCNH-8 in inducing immune escape from CD8+ T cell-mediated killing by upregulating PD-L1 in a miR-217/miR-3173 dependent manner, which also reveals a novel mechanism of PD-L1 regulation in HCC, and exosomal Lnc-CCNH-8 can serve as a predictive marker for immunotherapy response in HCC.