期刊
CANCER IMMUNOLOGY RESEARCH
卷 6, 期 7, 页码 835-847出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-17-0408
关键词
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资金
- Dutch Cancer Society [NKI 2012-5397]
- ZonMW [91610005]
In a mouse model of therapeutic DNA vaccination, we studied how the subcellular localization of vaccine protein impacts antigen delivery to professional antigen-presenting cells and efficiency of CTL priming. Cytosolic, membrane-bound, nuclear, and secretory versions of ZsGreen fluorescent protein, conjugated to MHC class I and II ovalbumin (OVA) epitopes, were expressed in keratinocytes by DNA vaccination into the skin. ZsGreen-OVA versions reached B cells in the skin-draining lymph node (dLN) that proved irrelevant for CTL priming. ZsGreen-OVA versions were also actively transported to the dLN by dendritic cells (DC). In the dLN, vaccine proteins localized to classical (c)DCs of the migratory XCR1(+) and XCR- subtypes, and-to a lesser extent-to LN-resident cDCs. Secretory ZsGreen-OVA induced the best antitumor CTL response, even though its delivery to cDCs in the dLN was significantly less efficient than for other vaccine proteins. Secretory ZsGreen-OVA protein proved superior in CTL priming, because it led to in vivo engagement of antigen-loaded XCR1(+), but not XCR1(-), cDCs. Secretory ZsGreen-OVA also maximally solicited CD4(+) T-cell help. The suboptimal CTL response to the other ZsGreen-OVA versions was improved by engaging costimulatory receptor CD27, which mimics CD4(+) T-cell help. Thus, in therapeutic DNA vaccination into the skin, mere inclusion of helper epitopes does not ensure delivery of CD4(+) T-cell help for the CTL response. Targeting of the vaccine protein to the secretory route of keratinocytes is required to engage XCR1(+) cDC and CD4(+) T-cell help and thus to promote CTL priming. (C) 2018 AACR.
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