PMID- 35186943
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220223
IS  - 2296-634X (Print)
IS  - 2296-634X (Electronic)
IS  - 2296-634X (Linking)
VI  - 9
DP  - 2021
TI  - Multi-Level Computational Modeling of Anti-Cancer Dendritic Cell Vaccination 
      Utilized to Select Molecular Targets for Therapy Optimization.
PG  - 746359
LID - 10.3389/fcell.2021.746359 [doi]
LID - 746359
AB  - Dendritic cells (DCs) can be used for therapeutic vaccination against cancer. The 
      success of this therapy depends on efficient tumor-antigen presentation to 
      cytotoxic T lymphocytes (CTLs) and the induction of durable CTL responses by the 
      DCs. Therefore, simulation of such a biological system by computational modeling 
      is appealing because it can improve our understanding of the molecular mechanisms 
      underlying CTL induction by DCs and help identify new strategies to improve 
      therapeutic DC vaccination for cancer. Here, we developed a multi-level model 
      accounting for the life cycle of DCs during anti-cancer immunotherapy. 
      Specifically, the model is composed of three parts representing different stages 
      of DC immunotherapy - the spreading and bio-distribution of intravenously 
      injected DCs in human organs, the biochemical reactions regulating the DCs' 
      maturation and activation, and DC-mediated activation of CTLs. We calibrated the 
      model using quantitative experimental data that account for the activation of key 
      molecular circuits within DCs, the bio-distribution of DCs in the body, and the 
      interaction between DCs and T cells. We showed how such a data-driven model can 
      be exploited in combination with sensitivity analysis and model simulations to 
      identify targets for enhancing anti-cancer DC vaccination. Since other previous 
      works show how modeling improves therapy schedules and DC dosage, we here focused 
      on the molecular optimization of the therapy. In line with this, we simulated the 
      effect in DC vaccination of the concerted modulation of combined intracellular 
      regulatory processes and proposed several possibilities that can enhance 
      DC-mediated immunogenicity. Taken together, we present a comprehensive 
      time-resolved multi-level model for studying DC vaccination in melanoma. Although 
      the model is not intended for personalized patient therapy, it could be used as a 
      tool for identifying molecular targets for optimizing DC-based therapy for 
      cancer, which ultimately should be tested in in vitro and in vivo experiments.
CI  - Copyright (c) 2022 Lai, Keller, Santos, Schaft, Dorrie and Vera.
FAU - Lai, Xin
AU  - Lai X
AD  - Laboratory of Systems Tumor Immunology, Department of Dermatology, 
      Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU) and Universitatsklinikum 
      Erlangen, Erlangen, Germany.
AD  - Deutsches Zentrum Immuntherapie and Comprehensive Cancer Center Erlangen-EMN, 
      Erlangen, Germany.
FAU - Keller, Christine
AU  - Keller C
AD  - Laboratory of Systems Tumor Immunology, Department of Dermatology, 
      Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU) and Universitatsklinikum 
      Erlangen, Erlangen, Germany.
FAU - Santos, Guido
AU  - Santos G
AD  - Laboratory of Systems Tumor Immunology, Department of Dermatology, 
      Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU) and Universitatsklinikum 
      Erlangen, Erlangen, Germany.
AD  - Departament of Biochemistry, Microbiology, Cell Biology and Genetics, Faculty of 
      Sciences, University of La Laguna, San Cristobal de La Laguna, Spain.
FAU - Schaft, Niels
AU  - Schaft N
AD  - Deutsches Zentrum Immuntherapie and Comprehensive Cancer Center Erlangen-EMN, 
      Erlangen, Germany.
AD  - RNA Group, Department of Dermatology, Friedrich-Alexander-Universitat 
      Erlangen-Nurnberg (FAU) and Universitatsklinikum Erlangen, Erlangen, Germany.
FAU - Dorrie, Jan
AU  - Dorrie J
AD  - Deutsches Zentrum Immuntherapie and Comprehensive Cancer Center Erlangen-EMN, 
      Erlangen, Germany.
AD  - RNA Group, Department of Dermatology, Friedrich-Alexander-Universitat 
      Erlangen-Nurnberg (FAU) and Universitatsklinikum Erlangen, Erlangen, Germany.
FAU - Vera, Julio
AU  - Vera J
AD  - Laboratory of Systems Tumor Immunology, Department of Dermatology, 
      Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU) and Universitatsklinikum 
      Erlangen, Erlangen, Germany.
AD  - Deutsches Zentrum Immuntherapie and Comprehensive Cancer Center Erlangen-EMN, 
      Erlangen, Germany.
LA  - eng
PT  - Journal Article
DEP - 20220202
PL  - Switzerland
TA  - Front Cell Dev Biol
JT  - Frontiers in cell and developmental biology
JID - 101630250
PMC - PMC8847669
OTO - NOTNLM
OT  - bio-distribution
OT  - cellular therapy
OT  - dendritic cell vaccine
OT  - gene networks
OT  - immunotherapy
OT  - kinetic modeling
OT  - melanoma
OT  - systems medicine
COIS- NS and JD are named as inventors on a patent on caIKK-RNA-electroporated DCs 
      (WO/2012/055551), which is held by the Friedrich-Alexander-Universitat 
      Erlangen-Nurnberg.
EDAT- 2022/02/22 06:00
MHDA- 2022/02/22 06:01
PMCR- 2021/01/01
CRDT- 2022/02/21 06:05
PHST- 2021/07/23 00:00 [received]
PHST- 2021/12/23 00:00 [accepted]
PHST- 2022/02/21 06:05 [entrez]
PHST- 2022/02/22 06:00 [pubmed]
PHST- 2022/02/22 06:01 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 746359 [pii]
AID - 10.3389/fcell.2021.746359 [doi]
PST - epublish
SO  - Front Cell Dev Biol. 2022 Feb 2;9:746359. doi: 10.3389/fcell.2021.746359. 
      eCollection 2021.