PMID- 30467420 OWN - NLM STAT- MEDLINE DCOM- 20200828 LR - 20210109 IS - 2042-0226 (Electronic) IS - 1672-7681 (Print) IS - 1672-7681 (Linking) VI - 16 IP - 10 DP - 2019 Oct TI - TLR9 agonist enhances radiofrequency ablation-induced CTL responses, leading to the potent inhibition of primary tumor growth and lung metastasis. PG - 820-832 LID - 10.1038/s41423-018-0184-y [doi] AB - Radiofrequency ablation (RFA) is the most common approach to thermal ablation for cancer therapy. Unfortunately, its efficacy is limited by incomplete ablation, and further optimization of RFA is required. Here, we demonstrate that incubation at 65 degrees C triggers more EG7 tumor cell death by necrosis than treatment at 45 degrees C, and the 65 degrees C-treated cells are more effective at inducing antigen-specific CD8(+) cytotoxic T lymphocyte (CTL) responses after injection in mice than the 45 degrees C-treated ones. Dendritic cells (DCs) that phagocytose 65 degrees C-treated EG7 cells become mature with upregulated MHCII and CD80 expression and are capable of efficiently inducing effector CTLs in mouse tumor models. RFA (65 degrees C) therapy of EG7 tumors induces large areas of tumor necrosis and stimulates CTL responses. This leads to complete regression of small (~100 mm(3)) tumors but fails to suppress the growth of larger (~350 mm(3)) tumors. The administration of the Toll-like receptor-9 (TLR9) agonist unmethylated cytosine-phosphorothioate-guanine oligonucleotide (CpG) to DCs phagocytosing 65 degrees C-treated EG7 cells enhances the expression of MHCII and CD40 on DCs as well as DC-induced stimulation of CTL responses. Importantly, the intratumoral administration of CpG following RFA also increases the frequencies of tumor-associated immunogenic CD11b(-)CD11c(+)CD103(+) DC2 and CD11b(+)F4/80(+)MHCII(+) M1 macrophages and increases CD4(+) and CD8(+) T-cell tumor infiltration, leading to enhanced CD4(+) T cell-dependent CTL responses and potent inhibition of primary RFA-treated or distant untreated tumor growth as well as tumor lung metastasis in mice bearing larger tumors. Overall, our data indicate that CpG administration, which enhances RFA-induced CTL responses and ultimately potentiates the inhibition of primary tumor growth and lung metastasis, is a promising strategy for improving RFA treatment, which may assist in optimizing this important cancer therapy. FAU - Xu, Aizhang AU - Xu A AD - Cancer Research, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada. AD - Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. FAU - Zhang, Lifeng AU - Zhang L AD - Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China. FAU - Yuan, Jingying AU - Yuan J AD - Cancer Research, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada. AD - Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. FAU - Babikr, Fatma AU - Babikr F AD - Cancer Research, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada. AD - Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. FAU - Freywald, Andrew AU - Freywald A AD - Department of Pathology, University of Saskatchewan, Saskatoon, SK, Canada. FAU - Chibbar, Rajni AU - Chibbar R AD - Department of Pathology, University of Saskatchewan, Saskatoon, SK, Canada. FAU - Moser, Michael AU - Moser M AD - Department of Surgery, University of Saskatchewan, Saskatoon, SK, Canada. FAU - Zhang, Wenjun AU - Zhang W AD - Department of Bioengineering, University of Saskatchewan, Saskatoon, SK, Canada. FAU - Zhang, Bing AU - Zhang B AD - Biomedical Science and Technology Research Center, School of Mechatronic Engineering and Automation, Shanghai University, Shanghai, China. FAU - Fu, Zhaoying AU - Fu Z AD - Department of Immunology, College of Medicine, Yian-An University, Yian-An, China. FAU - Xiang, Jim AU - Xiang J AD - Cancer Research, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada. jim.xiang@usask.ca. AD - Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. jim.xiang@usask.ca. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181122 PL - China TA - Cell Mol Immunol JT - Cellular & molecular immunology JID - 101242872 RN - 0 (Adjuvants, Immunologic) RN - 0 (Antigens, Neoplasm) RN - 0 (Dinucleoside Phosphates) RN - 0 (Toll-Like Receptor 9) RN - 2382-65-2 (cytidylyl-3'-5'-guanosine) SB - IM MH - Adjuvants, Immunologic/therapeutic use MH - Animals MH - Antigens, Neoplasm/immunology MH - CD8-Positive T-Lymphocytes/*immunology MH - Cell Line, Tumor MH - Cytotoxicity, Immunologic MH - Dendritic Cells/metabolism MH - Dinucleoside Phosphates/*therapeutic use MH - Hot Temperature MH - Humans MH - Lung/*pathology MH - Mice MH - Mice, Inbred C57BL MH - Necrosis MH - Neoplasm Metastasis MH - Neoplasm Transplantation MH - Radiofrequency Ablation/*methods MH - Toll-Like Receptor 9/agonists PMC - PMC6804546 OTO - NOTNLM OT - CTL response OT - RFA OT - TLR9 agonist OT - antitumor immunity OT - metastasis COIS- The authors declare no competing interests. EDAT- 2018/11/24 06:00 MHDA- 2020/08/29 06:00 PMCR- 2020/10/01 CRDT- 2018/11/24 06:00 PHST- 2018/08/29 00:00 [received] PHST- 2018/10/25 00:00 [accepted] PHST- 2018/11/24 06:00 [pubmed] PHST- 2020/08/29 06:00 [medline] PHST- 2018/11/24 06:00 [entrez] PHST- 2020/10/01 00:00 [pmc-release] AID - 10.1038/s41423-018-0184-y [pii] AID - 184 [pii] AID - 10.1038/s41423-018-0184-y [doi] PST - ppublish SO - Cell Mol Immunol. 2019 Oct;16(10):820-832. doi: 10.1038/s41423-018-0184-y. Epub 2018 Nov 22.