Journal
CANCER RESEARCH
Volume 75, Issue 6, Pages 986-995Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-2371
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Funding
- Natural Science Foundation of China [91029303, 31390433, 81273244]
- Ministry of Science & Technology of China (973 Basic Science Project) [2012CB519004]
- National Science & Technology Major Projects [2013ZX10002002-002]
- Chongqing Science and Technology Department (Basic Science Project) [cstc2013jcyjC10002]
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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)IL18R alpha(+) 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 IFN gamma 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 adminstration 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. (C)2015 AACR.
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