PMID- 33513928
OWN - NLM
STAT- MEDLINE
DCOM- 20210908
LR  - 20210908
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 3
DP  - 2021 Jan 27
TI  - Constitutively Activated DAP12 Induces Functional Anti-Tumor Activation and 
      Maturation of Human Monocyte-Derived DC.
LID - 10.3390/ijms22031241 [doi]
LID - 1241
AB  - Dendritic cells (DCs) are professional antigen presenting cells with a great 
      capacity for cross-presentation of exogenous antigens from which robust 
      anti-tumor immune responses ensue. However, this function is not always available 
      and requires DCs to first be primed to induce their maturation. In particular, in 
      the field of DC vaccine design, currently available methodologies have been 
      limited in eliciting a sustained anti-tumor immune response. Mechanistically, 
      part of the maturation response is influenced by the presence of stimulatory 
      receptors relying on ITAM-containing activating adaptor molecules like DAP12, 
      that modulates their function. We hypothesize that activating DAP12 in DC could 
      force their maturation and enhance their potential anti-tumor activity for 
      therapeutic intervention. For this purpose, we developed constitutively active 
      DAP12 mutants that can promote activation of monocyte-derived DC. Here we 
      demonstrate its ability to induce the maturation and activation of 
      monocyte-derived DCs which enhances migration, and T cell stimulation in vitro 
      using primary human cells. Moreover, constitutively active DAP12 stimulates a 
      strong immune response in a murine melanoma model leading to a reduction of tumor 
      burden. This provides proof-of-concept for investigating the pre-activation of 
      antigen presenting cells to enhance the effectiveness of anti-tumor 
      immunotherapies.
FAU - Dalton, Robert
AU  - Dalton R
AD  - Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
FAU - Calescibetta, Alexandra
AU  - Calescibetta A
AD  - Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
FAU - Zhou, Jun Min
AU  - Zhou JM
AD  - Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
FAU - Maurin, Michelle
AU  - Maurin M
AD  - Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
FAU - Ward, Grace
AU  - Ward G
AUID- ORCID: 0000-0003-4404-7727
AD  - Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
FAU - Trinh, Thu Le
AU  - Trinh TL
AUID- ORCID: 0000-0001-8517-4891
AD  - Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
FAU - Tu, Nhan
AU  - Tu N
AD  - Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
FAU - Gilvary, Danielle
AU  - Gilvary D
AD  - Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
FAU - Chen, Xianghong
AU  - Chen X
AD  - Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
FAU - Cheng, Pingyan
AU  - Cheng P
AD  - Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
FAU - Kostenko, Elena
AU  - Kostenko E
AD  - Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
FAU - Wei, Sheng
AU  - Wei S
AD  - Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
FAU - Wright, Kenneth L
AU  - Wright KL
AD  - Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
FAU - Eksioglu, Erika A
AU  - Eksioglu EA
AUID- ORCID: 0000-0003-4458-7192
AD  - Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
LA  - eng
GR  - K01 CA187020/CA/NCI NIH HHS/United States
GR  - P30 CA076292/CA/NCI NIH HHS/United States
GR  - P30CA076292/CA/NCI NIH HHS/United States
GR  - K01CA187020/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20210127
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cancer Vaccines)
RN  - 0 (Membrane Proteins)
RN  - 0 (Mutant Proteins)
RN  - 0 (TYROBP protein, human)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*genetics/immunology
MH  - Animals
MH  - Antigen-Presenting Cells/immunology
MH  - Cancer Vaccines/immunology
MH  - Cell Movement/genetics
MH  - Cell Proliferation/genetics
MH  - Dendritic Cells/*immunology
MH  - Humans
MH  - Immunity, Cellular/genetics/*immunology
MH  - Melanoma, Experimental/*immunology/pathology/therapy
MH  - Membrane Proteins/*genetics/immunology
MH  - Mice
MH  - Monocytes/immunology
MH  - Mutant Proteins/genetics/immunology
MH  - Tumor Burden/immunology
PMC - PMC7865632
OTO - NOTNLM
OT  - DC immunotherapy
OT  - constitutively active DAP12
OT  - human monocyte-derived dendritic cells
COIS- The S.W. laboratory received unrelated support from Celgene and Genentech. S.W. 
      has received unrelated support from Blackbird BioFinance, LLC. All other authors 
      have no conflict-of-interest to declare for this research. The funders had no 
      role in the design of the study; in the collection, analyses, or interpretation 
      of data; in the writing of the manuscript, or in the decision to publish the 
      results.
EDAT- 2021/01/31 06:00
MHDA- 2021/09/09 06:00
PMCR- 2021/01/27
CRDT- 2021/01/30 01:02
PHST- 2021/01/01 00:00 [received]
PHST- 2021/01/22 00:00 [revised]
PHST- 2021/01/22 00:00 [accepted]
PHST- 2021/01/30 01:02 [entrez]
PHST- 2021/01/31 06:00 [pubmed]
PHST- 2021/09/09 06:00 [medline]
PHST- 2021/01/27 00:00 [pmc-release]
AID - ijms22031241 [pii]
AID - ijms-22-01241 [pii]
AID - 10.3390/ijms22031241 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Jan 27;22(3):1241. doi: 10.3390/ijms22031241.