2024-03-28T22:39:54Zhttps://eprints.lib.hokudai.ac.jp/dspace-oai/requestoai:eprints.lib.hokudai.ac.jp:2115/713702022-11-17T02:08:08Zhdl_2115_20040hdl_2115_121Vaccine immunotherapy with ARNAX induces tumor-specific memory T cells and durable anti-tumor immunity in mouse modelsTakeda, YoheiYoshida, SumitoTakashima, KenIshii-Mugikura, NorikoShime, HiroakiSeya, TsukasaMatsumoto, Misakocancer immunotherapymemory CD8+ T cellPD-L1 blockadeToll-like receptor 3 adjuvanttumor microenvironment490Immunological checkpoint blockade therapies benefit a limited population of cancer patients. We have previously shown that vaccine immunotherapy with Toll-like receptor (TLR)3-adjuvant and tumor antigen overcomes anti-programmed death ligand-1 (PD-L1) resistance in mouse tumor models. In the present study, 4 different ovalbumin (OVA)-expressing tumor cell lines were implanted into syngeneic mice and subjected to anti-tumor immunotherapy using ARNAX and whole OVA protein. ARNAX is a TLR3-specific agonist that does not activate the mitochondrial antiviral-signaling protein (MAVS) pathway, and thus does not induce systemic inflammation. Dendritic cell priming and proliferative CTL were induced by ARNAX + OVA, but complete remission was achieved only in a PD-L1-low cell line of EG7. Addition of anti-PD-L1 antibody to the ARNAX + OVA therapy brought complete remission to another PD-L1-high subline of EG7. Tumor shrinkage but not remission was observed in MO5 in that regimen. We analyzed tumor cells and tumor-infiltrating immune cells to identify factors associated with successful ARNAX vaccine therapy. Tumors that responded to ARNAX therapy expressed high levels of MHC class I and low levels of PD-L1. The tumor-infiltrating immune cells in ARNAX-susceptible tumors contained fewer immunosuppressive myeloid cells with low PD-L1 expression. Combination with anti-PD-L1 antibody functioned not only within tumor sites but also within lymphoid tissues, augmenting the therapeutic efficacy of the ARNAX vaccine. Notably, ARNAX therapy induced memory CD8+ T cells and rejection of reimplanted tumors. Thus, ARNAX vaccine + anti-PD-L1 therapy enabled permanent remission against some tumors that stably present antigens.John Wiley & SonsJournal Articleapplication/pdfapplication/mswordhttp://hdl.handle.net/2115/71370https://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/71370/2/Takeda_et_al-2018-Cancer_Science.pdfhttps://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/71370/1/cas13649-sup-0001-Supinfo.doc1347-90321349-7006Cancer science1097211921292018-07enginfo:doi/10.1111/cas.13649http://creativecommons.org/licenses/by-nc/4.0/publisher