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.
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.
Cancer Res. 2015 Mar 15;75(6):986-95. doi: 10.1158/0008-5472.CAN-14-2371. Epub 2015 Jan 19.
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.
肝细胞癌 (HCC) 的免疫机制尚不清楚。在这里，我们表明 Toll 样受体 TLR2 抑制前炎症细胞因子 IL18 的产生，并保护小鼠免受 DEN 诱导的肝癌发生。在该方案中，Tlr2(-/-) 小鼠表现出更具侵袭性的 HCC 发展，伴随着 CD8(+) T 细胞功能受损。此外，在肿瘤发生之前，Tlr2(-/-) 小鼠肝脏中 Ly6C(high)IL18Rα(+)髓系来源的抑制细胞 (MDSC) 的数量增加。在这种情况下，MDSC 表现出更高的 iNOS 水平，可抑制 IFNγ 的产生和 CD8(+) T 细胞的体外增殖。值得注意的是，DEN 处理后 Tlr2(-/-) 肝细胞产生更多成熟的 IL18，足以驱动 MDSC 在该处积累。IL18 的给药足以诱导 MDSC 的积累，而 Tlr2(-/-) 小鼠中肝细胞特异性沉默 IL18 则降低了 MDSC 的比例，增加了功能 CD8(+) T 细胞的比例，并缓解了 HCC 的进展。IL18 的产生是由半胱天冬酶-8 介导的，因为其沉默的减少足以减弱 Tlr2(-/-) 小鼠中成熟 IL18 的水平。此外，TLR2 激动剂 Pam3CSK4 抑制半胱天冬酶-8 和 IL18 的表达，减少 MDSC，增加 CD8(+) T 细胞的功能，并促进 HCC 的消退。总的来说，我们的发现表明 TLR2 缺乏如何在肝癌发生过程中加速 IL18 介导的免疫抑制，为免疫控制提供了新的见解，这可能有助于设计有效的免疫疗法来治疗 HCC。
