Interleukin-27 signaling serves as an immunological checkpoint for innate cytotoxic cells to promote hepatocellular carcinoma

Aghayev, Turan, Mazitova, Aleksandra M., Fang, Jennifer R., Peshkova, Iuliia O., Rausch, Matthew, Hung, Manhsin, White, Kerry F., Masia, Ricard, Titerina, Elizaveta K., Fatkhullina, Aliia R., Cousineau, Isabelle, Turcotte, Simon, Zhigarev, Dmitry, Marchenko, Anastasiia, Khoziainova, Svetlana, Makhov, Petr, Tan, Yin Fei, Kossenkov, Andrew V., Wiest, David L., Stagg, John, Wang, Xin Wei, Campbell, Kerry S., Dzutsev, Amiran K., Trinchieri, Giorgio, Hill, Jonathan A., Grivennikov, Sergei I., Koltsova, Ekaterina K., Mazitova, Aleksandra M, Fang, Jennifer R, Peshkova, Iuliia O, White, Kerry F, Titerina, Elizaveta K, Fatkhullina, Aliia R, Kossenkov, Andrew V, Wiest, David L, Campbell, Kerry S, Dzutsev, Amiran K, Hill, Jonathan A, Grivennikov, Sergei I, Koltsova, Ekaterina K

While inflammatory mechanisms driving hepatocellular carcinoma (HCC) had been proposed, the regulators of anti-cancer immunity in HCC remain poorly understood. We found that IL-27 receptor (IL-27R) signaling promotes HCC development in vivo. High IL-27EBI3 cytokine or IL-27RA expression correlated with poor prognosis for patients with HCC. Loss of IL-27R suppressed HCC in vivo in two different models of hepatocarcinogenesis. Mechanistically, IL-27R signaling within the tumor microenvironment restrains the cytotoxicity of innate cytotoxic lymphocytes. IL-27R ablation enhanced their accumulation and activation, while depletion or functional impairment of innate cytotoxic cells abrogated the effect of IL-27R disruption. Pharmacological neutralization of IL-27 signaling increased infiltration of innate cytotoxic lymphocytes with upregulated cytotoxic molecules and reduced HCC development. Our data reveal an unexpected role of IL-27R signaling as an immunological checkpoint regulating innate cytotoxic lymphocytes and promoting HCC of different etiologies, thus indicating a therapeutic potential for IL-27 pathway blockade in HCC.