期刊
CANCER SCIENCE
卷 109, 期 7, 页码 2119-2129出版社
WILEY
DOI: 10.1111/cas.13649
关键词
cancer immunotherapy; memory CD8(+) T cell; PD-L1 blockade; Toll-like receptor 3 adjuvant; tumor microenvironment
类别
资金
- Japan Agency for Medical Research and Development [16nk0101327h0002]
- Japan Society for the Promotion of Science [17H06484]
- Grants-in-Aid for Scientific Research [17H06484] Funding Source: KAKEN
Immunological 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.
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