期刊
CANCER IMMUNOLOGY RESEARCH
卷 6, 期 9, 页码 1025-1038出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-17-0607
关键词
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资金
- Fannie & John Hertz Foundation
- NSF
- Siebel Scholarship
- Ragon Institute of MGH, MIT, and Harvard
- Mayo Clinic-Koch Institute Collaboration
- Koch Institute from the National Cancer Institute [P30-CA14051]
- Marble Center for Cancer Nanomedicine
- Koch Institute for Integrative Cancer Research
- Dana Farber/Harvard Cancer Center the V Foundation
- NIH [EB022433, CA174795, CA206218, CA172164]
- National Institute of General Medical Sciences [T32GM007753]
- U.S. Army Research Office
- U.S. Army Medical Research and Materiel Command
- Northwestern University
- Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource [NSF ECCS-1542205]
Antitumor T-cell responses have the potential to be curative in cancer patients, but the induction of potent T-cell immunity through vaccination remains a largely unmet goal of immunotherapy. We previously reported that the immunogenicity of peptide vaccines could be increased by maximizing delivery to lymph nodes (LNs), where T-cell responses are generated. This was achieved by conjugating the peptide to 1,2-distearoylsn-glycero-3-phosphoethanolamine-N-PEG (DSPE-PEG) to promote albumin binding, which resulted in enhanced lymphatic drainage and improved T-cell responses. Here, we expanded upon these findings and mechanistically dissected the properties that contribute to the potency of this amphiphile-vaccine (amph-vaccine). We found that multiple linkage chemistries could be used to link peptides with DSPE-PEG, and further, that multiple albumin-binding moieties conjugated to peptide antigens enhanced LN accumulation and subsequent T-cell priming. In addition to enhancing lymphatic trafficking, DSPE-PEG conjugation increased the stability of peptides in serum. DSPE-PEG peptides trafficked beyond immediate draining LNs to reach distal nodes, with antigen presented for at least a week in vivo, whereas soluble peptide presentation quickly decayed. Responses to amph-vaccines were not altered in mice deficient in the albumin-binding neonatal Fc receptor (FcRn), but required Batf3-dependent dendritic cells (DCs). Amph-peptides were processed by human DCs equivalently to unmodified peptides. These data define design criteria for enhancing the immunogenicity of molecular vaccines to guide the design of next-generation peptide vaccines. (C) 2018 AACR.
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