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Hepatology. 2019 Jun;69(6):2518-2532. doi: 10.1002/hep.30528. Epub 2019 Mar 13.

An Efficient Combination Immunotherapy for Primary Liver Cancer by Harmonized Activation of Innate and Adaptive Immunity in Mice.

Wen L1,2,3, Xin B1, Wu P1,2, Lin CH4, Peng C1,3, Wang G1, Lee J1, Lu LF4, Feng GS1.

Author information

1
Department of Pathology, Division of Biological Sciences and Moores Cancer Center, University of California at San Diego, La Jolla, CA.
2
Department of General Surgery, Second Affiliated Hospital of Zhejiang University, Hangzhou, P.R. China.
3
Department of Surgery, First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, P.R. China.
4
Division of Biological Sciences, Center for Microbiome Innovation and Moores Cancer Center, University of California at San Diego, La Jolla, CA.

Abstract

Immunotherapy with checkpoint inhibitors for liver cancer, while active in many clinical trials worldwide, may have uncertain outcomes due to the unique immunotolerant microenvironment of the liver. In previous experiments, we unexpectedly identified a robust liver tumor-preventive effect of a synthetic double-stranded RNA, polyinosinic-polycytidylic acid (polyIC), in mice. Herein we further demonstrate that polyIC given at the precancer stage effectively prevented liver tumorigenesis by activating natural killer cells, macrophages, and some T-cell subsets; no inhibitory effect was observed on tumor progression if injected after tumor initiation. Nevertheless, polyIC administration potently induced programmed death ligand 1 (PD-L1) expression in liver sinusoid endothelial cells, which prompted us to test a combined treatment of polyIC and PD-L1 antibody (Ab). Although injecting PD-L1 Ab alone did not show any therapeutic effect, injection of polyIC sensitized the hepatic response to PD-L1 blockade. Combination of polyIC and PD-L1 Ab resulted in sustained accumulation of active cluster of differentiation 8 cytotoxic T cells and robust liver tumor suppression and conferred a survival advantage in mice. These preclinical data in animal models suggest that, despite the low efficacy of PD-L1/PD-1 blockade alone, careful design of mechanism-based combinatorial immunotherapeutic protocols may shift the paradigm in liver cancer treatment by coordinating maximal activation of multiple innate and adaptive immune functions. Conclusion: We provide proof of principle for the development of an efficient prevention strategy of liver tumorigenesis and a powerful combination immunotherapy for primary liver cancer.

PMID:
30693544
PMCID:
PMC6541536
[Available on 2020-06-01]
DOI:
10.1002/hep.30528

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