title: TLR2 limits development of hepatocellular carcinoma by reducing IL18-mediated immunosuppression.
abstract: Immune mechanisms underlying hepatocellular carcinoma (HCC) are not well understood. Here, we show that the Toll-like receptor TLR2 inhibits production of the proinflammatory cytokine IL18 and protects mice from DEN-induced liver carcinogenesis. On this protocol, Tlr2(-/-) mice exhibited more aggressive HCC development associated with impaired CD8(+) T-cell function. Furthermore, Ly6C(high)IL18Rα(+) myeloid-derived suppressor cells (MDSC) were increased in number in the livers of Tlr2(-/-) mice before tumor onset. MDSC in this setting exhibited higher iNOS levels that could inhibit IFNγ production and CD8(+) T-cell proliferation in vitro. Notably, Tlr2(-/-) hepatocytes produced more mature IL18 after DEN treatment that was sufficient to drive MDSC accumulation there. IL18 administration was sufficient to induce accumulation of MDSC, whereas hepatocyte-specific silencing of IL18 in Tlr2(-/-) mice decreased the proportion of MDSC, increased the proportion of functional CD8(+) T cells, and alleviated HCC progression. IL18 production was mediated by caspase-8 insofar as the decrease in its silencing was sufficient to attenuate levels of mature IL18 in Tlr2(-/-) mice. Furthermore, the TLR2 agonist Pam3CSK4 inhibited both caspase-8 and IL18 expression, decreasing MDSC, increasing CD8(+) T-cell function, and promoting HCC regression. Overall, our findings show how TLR2 deficiency accelerates IL18-mediated immunosuppression during liver carcinogenesis, providing new insights into immune control that may assist the design of effective immunotherapies to treat HCC.
authors.affiliation: Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: Shinan
authors.initials: S
authors.lastname: Li
authors.affiliation: Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, China. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Sun
authors.affiliation: Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: Yongyan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, China. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China.
authors.forename: Haiming
authors.initials: H
authors.lastname: Wei
authors.affiliation: Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, China. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. tzg@ustc.edu.cn.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D053181:Caspase 8 / Q000502:physiology; D007108:Immune Tolerance; D020382:Interleukin-18 / Q000502:physiology*; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000502:physiology*
chemical_list: D020382:Interleukin-18; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C505526:Casp8 protein, mouse; D053181:Caspase 8