PMID- 34821951
OWN - NLM
STAT- MEDLINE
DCOM- 20220614
LR  - 20220616
IS  - 1432-0851 (Electronic)
IS  - 0340-7004 (Print)
IS  - 0340-7004 (Linking)
VI  - 71
IP  - 7
DP  - 2022 Jul
TI  - Blood DCs activated with R848 and poly(I:C) induce antigen-specific immune 
      responses against viral and tumor-associated antigens.
PG  - 1705-1718
LID - 10.1007/s00262-021-03109-w [doi]
AB  - Monocyte-derived Dendritic cells (DCs) have successfully been employed to induce 
      immune responses against tumor-associated antigens in patients with various 
      cancer entities. However, objective clinical responses have only been achieved in 
      a minority of patients. Additionally, generation of GMP-compliant DCs requires 
      time- and labor-intensive cell differentiation. In contrast, Blood DCs (BDCs) 
      require only minimal ex vivo handling, as differentiation occurs in vivo 
      resulting in potentially better functional capacities and survival. We aimed to 
      identify a protocol for optimal in vitro activation of BDCs including the three 
      subsets pDCs, cDC1s, and cDC2s. We evaluated several TLR ligand combinations and 
      demonstrated that polyinosinic:polycytidylic acid [poly(I:C)] and R848, ligands 
      for TLR3 and TLR7/8, respectively, constituted the optimal combination for 
      inducing a positive co-stimulatory profile in all BDC subsets. In addition, TLR3 
      and TLR7/8 activation led to high secretion of IFN-alpha and IL-12p70. Simultaneous 
      as opposed to separate tailored activation of pDCs and cDCs increased 
      immunostimulatory capacities, suggesting that BDC subsets engage in synergistic 
      cross-talk during activation. Stimulation of BDCs with this protocol resulted in 
      enhanced migration, high NK-cell activation, and potent antigen-specific T-cell 
      induction.We conclude that simultaneous activation of all BDC subsets with a 
      combination of R848 + poly(I:C) generates highly immunostimulatory DCs. These 
      results support further investigation and clinical testing, as standalone or in 
      conjunction with other immunotherapeutic strategies including adoptive T-cell 
      transfer and checkpoint inhibition.
CI  - (c) 2021. The Author(s).
FAU - Hanel, Gerulf
AU  - Hanel G
AUID- ORCID: 0000-0003-4685-6499
AD  - Department of Medicine III, University Hospital, LMU Munich, Marchioninistr. 15, 
      81377, Munich, Germany.
AD  - Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, 
      Germany.
FAU - Angerer, Caroline
AU  - Angerer C
AD  - Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany.
FAU - Petry, Katja
AU  - Petry K
AD  - Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany.
FAU - Lichtenegger, Felix S
AU  - Lichtenegger FS
AUID- ORCID: 0000-0003-3990-1802
AD  - Department of Medicine III, University Hospital, LMU Munich, Marchioninistr. 15, 
      81377, Munich, Germany.
AD  - Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, 
      Germany.
AD  - Roche Innovation Center Munich, Penzberg, Germany.
FAU - Subklewe, Marion
AU  - Subklewe M
AUID- ORCID: 0000-0001-9154-9469
AD  - Department of Medicine III, University Hospital, LMU Munich, Marchioninistr. 15, 
      81377, Munich, Germany. marion.subklewe@med.uni-muenchen.de.
AD  - Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, 
      Germany. marion.subklewe@med.uni-muenchen.de.
AD  - German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 
      Heidelberg, Germany. marion.subklewe@med.uni-muenchen.de.
LA  - eng
GR  - SFB1243/deutsche forschungsgemeinschaft/
GR  - SU197/3-1/deutsche forschungsgemeinschaft/
GR  - 2018.087.1/wilhelm sander-stiftung/
PT  - Journal Article
DEP - 20211125
PL  - Germany
TA  - Cancer Immunol Immunother
JT  - Cancer immunology, immunotherapy : CII
JID - 8605732
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Antigens, Viral)
RN  - 0 (Toll-Like Receptor 3)
RN  - 0 (Toll-Like Receptor 7)
RN  - 0 (Toll-Like Receptor 8)
RN  - O84C90HH2L (Poly I-C)
SB  - IM
MH  - *Antigens, Neoplasm/immunology
MH  - *Antigens, Viral/immunology
MH  - *Dendritic Cells
MH  - Humans
MH  - Lymphocyte Activation
MH  - *Poly I-C/pharmacology
MH  - Toll-Like Receptor 3
MH  - Toll-Like Receptor 7
MH  - Toll-Like Receptor 8
PMC - PMC8614222
OTO - NOTNLM
OT  - Blood dendritic cells
OT  - Conventional dendritic cells
OT  - Immunotherapy
OT  - Plasmacytoid dendritic cells
OT  - Toll-like receptors
COIS- G.H. declares no conflicts of interest. C.A. and K.P. are employed by Miltenyi 
      Biotec. F.S.L. is employed by Hoffmann-La Roche. M.S. has received industry 
      research support from Amgen, Gilead, Miltenyi Biotec, Morphosys, Roche, and 
      Seattle Genetics, and has served as a consultant/advisor to Amgen, BMS, Celgene, 
      Gilead, Pfizer, Novartis, and Roche. She sits on the advisory boards of Amgen, 
      Celgene, Gilead, Janssen, Novartis, Pfizer, and Seattle Genetics, and serves on 
      the speakers' bureau at Amgen, Celgene, Gilead, Janssen, and Pfizer.
EDAT- 2021/11/26 06:00
MHDA- 2022/06/15 06:00
PMCR- 2021/11/25
CRDT- 2021/11/25 12:17
PHST- 2021/06/29 00:00 [received]
PHST- 2021/11/09 00:00 [accepted]
PHST- 2021/11/26 06:00 [pubmed]
PHST- 2022/06/15 06:00 [medline]
PHST- 2021/11/25 12:17 [entrez]
PHST- 2021/11/25 00:00 [pmc-release]
AID - 10.1007/s00262-021-03109-w [pii]
AID - 3109 [pii]
AID - 10.1007/s00262-021-03109-w [doi]
PST - ppublish
SO  - Cancer Immunol Immunother. 2022 Jul;71(7):1705-1718. doi: 
      10.1007/s00262-021-03109-w. Epub 2021 Nov 25.