报告主题：TLR9 agonist enhances radiofrequency ablation-induced CTL responses leading to potent inhibition of primary tumor growth and lung metastasis/对于免疫佐剂CpG坛强 RFA界导肿瘤消融疗法引起的抗肿瘤免疫反应的研究

报告时间：2018年6月19日13：00 - 15：00

报告地点：校本部A楼123室

主讲人： Prof. Jim Xiang, Division of Oncology, University of Saskatchewan, Canada

内容简介：

Radiofrequency ablation (RFA) is the most common approach in thermal ablation cancer therapy. Unfortunately, its efficacy is limited by incomplete ablation, and further optimization of RFA is required. Here, we demonstrate that incubation at 65^oC triggers more EG7 tumor cell-death by necrosis than treatment at 45^oC, and these cells are more effective after injection in mice in inducing antigen-specific CD8⁺ cytotoxic T lymphocyte (CTL) responses than 45^oC-treated ones. Dendritic cells (DCs) phagocytosing 65^oC-treated EG7 tumor-cells become mature with upregulated Ia^b and CD80 expression, capable of efficiently inducing effector CTLs in mouse tumor models.  RFA (65^oC) therapy of EG7 tumors induces large areas of tumor necrosis and stimulates CTL responses. This leads to complete regression of small-size (~100 mm³) EG7 tumors, but fails to suppress larger-size (~350 mm³) ones. Administration of Toll-like receptor-9 (TLR9) agonist, unmethylated cytosine-phosphorothioate-guanine (CpG) oligonucleotide, to DCs phagocytosing 65^oC-treated EG7-cells, enhances both expression of Ia^b, CD40 and CD80 by DCs and DC-induced stimulation of CTL responses. Importantly, intratumoral administration of CpG following RFA also induces intratumoral DC maturation, switches tolerogenic CD11c⁺CD11b⁺ DC1 to immunogenic CD11c⁺CD103⁺ DC2 and increases CD4⁺ and CD8⁺ T-cell tumor infiltration, leading to enhanced CD4⁺ T-cell-dependent CTL responses and potent inhibition of primary tumor growth and tumor lung metastasis in mice bearing larger-size tumors. Overall, our data indicate that CpG administration, which enhances RFA-induced CTL responses and ultimately potentiates inhibition of primary tumor growth and lung metastasis, is a promising strategy for improving RFA treatment, which may assist in optimising this important cancer therapy.