Constitutively Activated DAP12 Induces Functional Anti-Tumor Activation and Maturation of Human Monocyte-Derived DC
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 pa...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/3/1241 |
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| author | Robert Dalton Alexandra Calescibetta Jun Min Zhou Michelle Maurin Grace Ward Thu Le Trinh Nhan Tu Danielle Gilvary Xianghong Chen Pingyan Cheng Elena Kostenko Sheng Wei Kenneth L. Wright Erika A. Eksioglu |
| author_facet | Robert Dalton Alexandra Calescibetta Jun Min Zhou Michelle Maurin Grace Ward Thu Le Trinh Nhan Tu Danielle Gilvary Xianghong Chen Pingyan Cheng Elena Kostenko Sheng Wei Kenneth L. Wright Erika A. Eksioglu |
| author_sort | Robert Dalton |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T03:31:25Z |
| format | Article |
| id | doaj.art-55956b22ad4443f2bf311ec3923596e6 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T03:31:25Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-55956b22ad4443f2bf311ec3923596e62023-12-03T14:55:20ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-01-01223124110.3390/ijms22031241Constitutively Activated DAP12 Induces Functional Anti-Tumor Activation and Maturation of Human Monocyte-Derived DCRobert Dalton0Alexandra Calescibetta1Jun Min Zhou2Michelle Maurin3Grace Ward4Thu Le Trinh5Nhan Tu6Danielle Gilvary7Xianghong Chen8Pingyan Cheng9Elena Kostenko10Sheng Wei11Kenneth L. Wright12Erika A. Eksioglu13Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USADepartment of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USADepartment of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USADepartment of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USADepartment of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USADepartment of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USADepartment of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USADepartment of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USADepartment of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USADepartment of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USADepartment of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USADepartment of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USADepartment of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USADepartment of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USADendritic 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.https://www.mdpi.com/1422-0067/22/3/1241human monocyte-derived dendritic cellsconstitutively active DAP12DC immunotherapy |
| spellingShingle | Robert Dalton Alexandra Calescibetta Jun Min Zhou Michelle Maurin Grace Ward Thu Le Trinh Nhan Tu Danielle Gilvary Xianghong Chen Pingyan Cheng Elena Kostenko Sheng Wei Kenneth L. Wright Erika A. Eksioglu Constitutively Activated DAP12 Induces Functional Anti-Tumor Activation and Maturation of Human Monocyte-Derived DC International Journal of Molecular Sciences human monocyte-derived dendritic cells constitutively active DAP12 DC immunotherapy |
| title | Constitutively Activated DAP12 Induces Functional Anti-Tumor Activation and Maturation of Human Monocyte-Derived DC |
| title_full | Constitutively Activated DAP12 Induces Functional Anti-Tumor Activation and Maturation of Human Monocyte-Derived DC |
| title_fullStr | Constitutively Activated DAP12 Induces Functional Anti-Tumor Activation and Maturation of Human Monocyte-Derived DC |
| title_full_unstemmed | Constitutively Activated DAP12 Induces Functional Anti-Tumor Activation and Maturation of Human Monocyte-Derived DC |
| title_short | Constitutively Activated DAP12 Induces Functional Anti-Tumor Activation and Maturation of Human Monocyte-Derived DC |
| title_sort | constitutively activated dap12 induces functional anti tumor activation and maturation of human monocyte derived dc |
| topic | human monocyte-derived dendritic cells constitutively active DAP12 DC immunotherapy |
| url | https://www.mdpi.com/1422-0067/22/3/1241 |
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