title: Shikonin-enhanced cell immunogenicity of tumor vaccine is mediated by the differential effects of DAMP components.
abstract: BACKGROUND
  The tumor cell lysate-pulsed, dendritic cell (DC)-based cancer vaccine approaches are being actively evaluated for application to cancer immunotherapy, hopefully at a personalized medicine base. There is apparently an emerging technical problem however, the lack of highly efficacious potency in activation of patient's DCs for T-cell priming and the associated process for presenting tumor immunogenicity.
  
  
  METHODS
  One strategy to address this is to consider the manipulation of the tumor immunogenic cells death (ICD) complex ex-vivo for maximal activation of DC efficacy. In our previous study we showed that phytochemical shikonin (SK) can drastically enhance ICD activity in mouse tumor cells treated ex-vivo, and the resultant tumor cell lysate (TCL) can effectively augment such SK-TCL pulsed DC vaccine activity in vivo in anti-tumor activities. In this study, we investigated the specifics and the multi-functional effects of various damaged associated molecular pattern (DAMP) components of the ICD complex for their participation, roles and potential cross talks in activating DCs, as measured by five different functional assays.
  
  
  RESULTS
  Among three DAMPs tested, HSP70 and CRT mediate a key role in SK-TCL-induced DC immunity for both CD4(+) and CD8(+) T cell proliferations in vitro. HSP70 is the most important component, followed by CRT, then HMGB1 in facilitating DC immunity on suppressing metastasis of mouse 4 T1 mammary tumors and prolonging survival in test mice. Only HSP70, but not CRT or HMGB1, is effective for the suppression of both granulocytic and monocytic MDSC populations in vivo. Both HSP70 and HMGB1, but not CRT, are essential in activating the expression of three key ICD molecules-associated receptors on test DCs. Each of the three test ICD proteins can exhibit a distinguishable pattern in stimulating the expression of four key chemokines in test DCs.
  
  
  CONCLUSIONS
  Our findings on the differential roles or effect of various ICD components in activating vaccinated DCs may help formulate new strategies for future cancer vaccine designs.
authors.affiliation: Graduate Institute of Injury Prevention and Control, Taipei Medical University, Taipei, Taiwan.|Department of Neurosurgery, Taipei Medical University - Wan Fang Hospital, Taipei, Taiwan.|Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.|Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan.|Taiwan International Graduate Program (TIGP), Molecular and Biological Agricultural Sciences Program, Academia Sinica, Taipei, Taiwan.
authors.forename: Tien-Jen
authors.initials: TJ
authors.lastname: Lin
authors.affiliation: Department of Neurosurgery, Taipei Medical University - Wan Fang Hospital, Taipei, Taiwan.|Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Hsin-Ting
authors.initials: HT
authors.lastname: Lin
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Chang
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.|Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan.|Taiwan International Graduate Program (TIGP), Molecular and Biological Agricultural Sciences Program, Academia Sinica, Taipei, Taiwan.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Mitapalli S
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.|Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan.|Taiwan International Graduate Program (TIGP), Molecular and Biological Agricultural Sciences Program, Academia Sinica, Taipei, Taiwan.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsiao
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan. yinshuyi@gate.sinica.edu.tw.
authors.forename: Shu-Yi
authors.initials: SY
authors.lastname: Yin
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan. nsyang@gate.sinica.edu.tw.|Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan. nsyang@gate.sinica.edu.tw.|Taiwan International Graduate Program (TIGP), Molecular and Biological Agricultural Sciences Program, Academia Sinica, Taipei, Taiwan. nsyang@gate.sinica.edu.tw.|Room 641, Agricultural Biotechnology Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Nankang, Taipei, Taiwan. nsyang@gate.sinica.edu.tw.
authors.forename: Ning-Sun
authors.initials: NS
authors.lastname: Yang
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D024243:HMGB1 Protein / Q000235:genetics / Q000276:immunology; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy; D051379:Mice; D009285:Naphthoquinones / Q000008:administration & dosage*; D057285:Precision Medicine; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D024243:HMGB1 Protein; D018840:HSP70 Heat-Shock Proteins; D009285:Naphthoquinones; C016101:shikonin