PMID- 35688559
OWN - NLM
STAT- MEDLINE
DCOM- 20220614
LR  - 20220716
IS  - 2051-1426 (Electronic)
IS  - 2051-1426 (Linking)
VI  - 10
IP  - 6
DP  - 2022 Jun
TI  - Combinations of Toll-like receptor 8 agonist TL8-506 activate human tumor-derived 
      dendritic cells.
LID - 10.1136/jitc-2021-004268 [doi]
LID - e004268
AB  - BACKGROUND: Dendritic cells (DCs) are professional antigen presenting cells that 
      initiate immune defense to pathogens and tumor cells. Human tumors contain only 
      few DCs that mostly display a non-activated phenotype. Hence, activation of 
      tumor-associated DCs may improve efficacy of cancer immunotherapies. Toll-like 
      receptor (TLR) agonists and interferons are known to promote DC maturation. 
      However, it is unclear if DCs in human tumors respond to activation signals and 
      which stimuli induce the optimal activation of human tumor DCs. METHODS: We first 
      screened combinations of TLR agonists, a STING agonist and interferons (IFNs) for 
      their ability to activate human conventional DCs (cDCs). Two combinations: 
      TL8-506 (a TLR8 agonist)+IFN-gamma and TL8-506+Poly(I:C) (a TLR3 agonist) were 
      studied in more detail. cDC1s and cDC2s derived from cord blood stem cells, blood 
      or patient tumor samples were stimulated with either TL8-506+IFN-gamma or 
      TL8-506+Poly(I:C). Different activation markers were analyzed by ELISA, flow 
      cytometry, NanoString nCounter Technology or single-cell RNA-sequencing. T cell 
      activation and migration assays were performed to assess functional consequences 
      of cDC activation. RESULTS: We show that TL8-506 synergized with IFN-gamma or 
      Poly(I:C) to induce high expression of different chemokines and cytokines 
      including interleukin (IL)-12p70 in human cord blood and blood cDC subsets in a 
      combination-specific manner. Importantly, both combinations induced the 
      activation of cDC subsets in patient tumor samples ex vivo. The expression of 
      immunostimulatory genes important for anticancer responses including CD40, IFNB1, 
      IFNL1, IL12A and IL12B were upregulated on stimulation. Furthermore, chemokines 
      associated with CD8(+) T cell recruitment were induced in tumor-derived cDCs in 
      response to TL8-506 combinations. In vitro activation and migration assays 
      confirmed that stimulated cDCs induce T cell activation and migration. 
      CONCLUSIONS: Our data suggest that cord blood-derived and blood-derived cDCs are 
      a good surrogate to study treatment responses in human tumor cDCs. While most 
      cDCs in human tumors display a non-activated phenotype, TL8-506 combinations 
      drive human tumor cDCs towards an immunostimulatory phenotype associated with Th1 
      responses on stimulation. Hence, TL8-506-based combinations may be promising 
      candidates to initiate or boost antitumor responses in patients with cancer.
CI  - (c) Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - He, Mi
AU  - He M
AUID- ORCID: 0000-0002-8271-6672
AD  - Roche Pharma Research and Early Development, Roche Innovation Center Zurich, 
      Schlieren, Switzerland mi.he@roche.com stephan.gasser@roche.com.
FAU - Soni, Bhavesh
AU  - Soni B
AD  - Roche Pharma Research and Early Development, Roche Innovation Center Basel, 
      Basel, Switzerland.
FAU - Schwalie, Petra C
AU  - Schwalie PC
AD  - Roche Pharma Research and Early Development, Roche Innovation Center Basel, 
      Basel, Switzerland.
FAU - Husser, Tamara
AU  - Husser T
AD  - Roche Pharma Research and Early Development, Roche Innovation Center Zurich, 
      Schlieren, Switzerland.
FAU - Waltzinger, Caroline
AU  - Waltzinger C
AD  - Roche Pharma Research and Early Development, Roche Innovation Center Zurich, 
      Schlieren, Switzerland.
FAU - De Silva, Duvini
AU  - De Silva D
AD  - Roche Pharma Research and Early Development, Roche Innovation Center Zurich, 
      Schlieren, Switzerland.
FAU - Prinz, Ylva
AU  - Prinz Y
AD  - Roche Pharma Research and Early Development, Roche Innovation Center Zurich, 
      Schlieren, Switzerland.
FAU - Krumpelmann, Laura
AU  - Krumpelmann L
AD  - Roche Pharma Research and Early Development, Roche Innovation Center Munich, 
      Penzberg, Germany.
FAU - Calabro, Samuele
AU  - Calabro S
AD  - Roche Pharma Research and Early Development, Roche Innovation Center Zurich, 
      Schlieren, Switzerland.
FAU - Matos, Ines
AU  - Matos I
AD  - Roche Pharma Research and Early Development, Roche Innovation Center Zurich, 
      Schlieren, Switzerland.
FAU - Trumpfheller, Christine
AU  - Trumpfheller C
AD  - Roche Pharma Research and Early Development, Roche Innovation Center Zurich, 
      Schlieren, Switzerland.
FAU - Bacac, Marina
AU  - Bacac M
AD  - Roche Pharma Research and Early Development, Roche Innovation Center Zurich, 
      Schlieren, Switzerland.
FAU - Umana, Pablo
AU  - Umana P
AD  - Roche Pharma Research and Early Development, Roche Innovation Center Zurich, 
      Schlieren, Switzerland.
FAU - Levesque, Mitchell P
AU  - Levesque MP
AD  - Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
FAU - Dummer, Reinhard
AU  - Dummer R
AUID- ORCID: 0000-0002-2279-6906
AD  - Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
FAU - van den Broek, Maries
AU  - van den Broek M
AUID- ORCID: 0000-0002-9489-3692
AD  - Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
FAU - Gasser, Stephan
AU  - Gasser S
AD  - Roche Pharma Research and Early Development, Roche Innovation Center Zurich, 
      Schlieren, Switzerland mi.he@roche.com stephan.gasser@roche.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Immunother Cancer
JT  - Journal for immunotherapy of cancer
JID - 101620585
RN  - 0 (Adjuvants, Immunologic)
RN  - 0 (Cytokines)
RN  - 0 (Toll-Like Receptor 8)
RN  - 187348-17-0 (Interleukin-12)
RN  - 82115-62-6 (Interferon-gamma)
RN  - O84C90HH2L (Poly I-C)
SB  - IM
MH  - Adjuvants, Immunologic/pharmacology
MH  - Cytokines/metabolism
MH  - Dendritic Cells
MH  - Humans
MH  - Interferon-gamma/metabolism/pharmacology
MH  - Interleukin-12/metabolism
MH  - *Neoplasms
MH  - Poly I-C/metabolism/pharmacology
MH  - *Toll-Like Receptor 8
PMC - PMC9189853
OTO - NOTNLM
OT  - dendritic cells
OT  - drug therapy, combination
OT  - immunity, innate
OT  - immunotherapy
OT  - interferon inducers
COIS- Competing interests: All authors, except MPL, RD and MvdB are employees of Roche.
EDAT- 2022/06/11 06:00
MHDA- 2022/06/15 06:00
PMCR- 2022/06/10
CRDT- 2022/06/10 21:07
PHST- 2022/04/27 00:00 [accepted]
PHST- 2022/06/10 21:07 [entrez]
PHST- 2022/06/11 06:00 [pubmed]
PHST- 2022/06/15 06:00 [medline]
PHST- 2022/06/10 00:00 [pmc-release]
AID - jitc-2021-004268 [pii]
AID - 10.1136/jitc-2021-004268 [doi]
PST - ppublish
SO  - J Immunother Cancer. 2022 Jun;10(6):e004268. doi: 10.1136/jitc-2021-004268.