PMID- 34282787
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210723
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 13
IP  - 13
DP  - 2021 Jul 5
TI  - Alpha-Fetoprotein- and CD40Ligand-Expressing Dendritic Cells for Immunotherapy of 
      Hepatocellular Carcinoma.
LID - 10.3390/cancers13133375 [doi]
LID - 3375
AB  - Dendritic cells (DC) as professional antigen presenting cells are able to prime 
      T-cells against the tumor-associated antigen alpha-fetoprotein (AFP) for 
      immunotherapy of hepatocellular carcinoma (HCC). However, a strong 
      immunosuppressive tumor environment limits their efficacy in patients. The 
      co-stimulation with CD40Ligand (CD40L) is critical in the maturation of DC and 
      T-cell priming. In this study, the impact of intratumoral (i.t.) CD40L-expressing 
      DC to improve vaccination with murine (m)AFP-transduced DC (Ad-mAFP-DC) was 
      analyzed in subcutaneous (s.c.) and orthotopic murine HCC. Murine DC were 
      adenovirally transduced with Ad-mAFP or Ad-CD40L. Hepa129-mAFP-cells were 
      injected into the right flank or the liver of C3H-mice to induce subcutaneous 
      (s.c.) and orthotopic HCC. For treatments, 10(6) Ad-mAFP-transduced DC were 
      inoculated s.c. followed by 10(6) CD40L-expressing DC injected intratumorally 
      (i.t.). S.c. inoculation with Ad-mAFP-transduced DC, as vaccine, induced a delay 
      of tumor-growth of AFP-positive HCC compared to controls. When s.c.-inoculation 
      of Ad-mAFP-DC was combined with i.t.-application of Ad-CD40L-DC synergistic 
      antitumoral effects were observed and complete remissions and long-term survival 
      in 62% of tumor-bearing animals were achieved. Analysis of the tumor environment 
      at different time points revealed that s.c.-vaccination with Ad-mAFP-DC seems to 
      stimulate tumor-specific effector cells, allowing an earlier recruitment of 
      effector T-cells and a Th1 shift within the tumors. After i.t. co-stimulation 
      with Ad-CD40L-DC, production of Th1-cytokines was strongly increased and 
      accompanied by a robust tumor infiltration of mature DC, activated CD4(+)-, 
      CD8(+)-T-cells as well as reduction of regulatory T-cells. Moreover, Ad-CD40L-DC 
      induced tumor cell apoptosis. Intratumoral co-stimulation with CD40L-expressing 
      DC significantly improves vaccination with Ad-mAFP-DC in pre-established HCC in 
      vivo. Combined therapy caused an early and strong Th1-shift in the tumor 
      environment as well as higher tumor apoptosis, leading to synergistic tumor 
      regression of HCC. Thus, CD40L co-stimulation represents a promising tool for 
      improving DC-based immunotherapy of HCC.
FAU - Vogt, Annabelle
AU  - Vogt A
AD  - Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, 
      Germany.
FAU - Sadeghlar, Farsaneh
AU  - Sadeghlar F
AD  - Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, 
      Germany.
FAU - Ayub, Tiyasha H
AU  - Ayub TH
AD  - Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, 
      Germany.
FAU - Schneider, Carlo
AU  - Schneider C
AD  - Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, 
      Germany.
FAU - Mohring, Christian
AU  - Mohring C
AUID- ORCID: 0000-0001-7651-4401
AD  - Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, 
      Germany.
FAU - Zhou, Taotao
AU  - Zhou T
AD  - Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, 
      Germany.
FAU - Mahn, Robert
AU  - Mahn R
AUID- ORCID: 0000-0001-8312-6511
AD  - Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, 
      Germany.
FAU - Bartels, Alexandra
AU  - Bartels A
AD  - Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, 
      Germany.
FAU - Praktiknjo, Michael
AU  - Praktiknjo M
AUID- ORCID: 0000-0001-7033-9956
AD  - Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, 
      Germany.
FAU - Kornek, Miroslaw T
AU  - Kornek MT
AUID- ORCID: 0000-0002-1682-1765
AD  - Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, 
      Germany.
FAU - Toma, Marieta
AU  - Toma M
AD  - Department of Pathology, University Hospital of Bonn, 53127 Bonn, Germany.
FAU - Schmidt-Wolf, Ingo G H
AU  - Schmidt-Wolf IGH
AD  - Department of Integrated Oncology (CIO), University of Bonn, 53127 Bonn, Germany.
FAU - Branchi, Vittorio
AU  - Branchi V
AUID- ORCID: 0000-0002-6182-835X
AD  - Department of Visceral Surgery, University Hospital of Bonn, 53127 Bonn, Germany.
FAU - Matthaei, Hanno
AU  - Matthaei H
AD  - Department of Visceral Surgery, University Hospital of Bonn, 53127 Bonn, Germany.
FAU - Kalff, Jorg C
AU  - Kalff JC
AD  - Department of Visceral Surgery, University Hospital of Bonn, 53127 Bonn, Germany.
FAU - Strassburg, Christian P
AU  - Strassburg CP
AD  - Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, 
      Germany.
FAU - Gonzalez-Carmona, Maria A
AU  - Gonzalez-Carmona MA
AUID- ORCID: 0000-0003-3956-1457
AD  - Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, 
      Germany.
LA  - eng
GR  - 109255/Deutsche Krebshilfe/
GR  - GO 1847/1-2/Deutsche Forschungsgemeinschaft/
GR  - BONFOR/University Hospital of Bonn/
PT  - Journal Article
DEP - 20210705
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC8269346
OTO - NOTNLM
OT  - CD40Ligand
OT  - alpha-fetoprotein
OT  - dendritic cells
OT  - hepatocellular carcinoma
OT  - subcutaneous and orthotopic murine HCC
COIS- The authors of this study do not have anything to disclose regarding funding from 
      industry or conflict of interest with respect to this manuscript. However, 
      M.A.G.-C. has contributed to advisory boards for Roche, Eisai, BMS, MSD and AZ. 
      None of the other authors have any potential conflicts (financial, professional, 
      or personal) that are relevant to the manuscript.
EDAT- 2021/07/21 06:00
MHDA- 2021/07/21 06:01
PMCR- 2021/07/05
CRDT- 2021/07/20 08:41
PHST- 2021/05/12 00:00 [received]
PHST- 2021/06/28 00:00 [revised]
PHST- 2021/06/29 00:00 [accepted]
PHST- 2021/07/20 08:41 [entrez]
PHST- 2021/07/21 06:00 [pubmed]
PHST- 2021/07/21 06:01 [medline]
PHST- 2021/07/05 00:00 [pmc-release]
AID - cancers13133375 [pii]
AID - cancers-13-03375 [pii]
AID - 10.3390/cancers13133375 [doi]
PST - epublish
SO  - Cancers (Basel). 2021 Jul 5;13(13):3375. doi: 10.3390/cancers13133375.