DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells
Background Conventional type 1 dendritic cells (cDC1s) are central to antitumor immunity and their presence in the tumor microenvironment associates with improved outcomes in patients with cancer. DNGR-1 (CLEC9A) is a dead cell-sensing receptor highly restricted to cDC1s. DNGR-1 has been involved in...
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BMJ Publishing Group
2021-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/9/5/e002054.full |
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| author | Ignacio Melero Ruth Conde-Garrosa David Sancho Santos Mañes Alfonso R Sanchez-Paulete Francisco J Cueto Carlos del Fresno Paola Brandi Alexis J. Combes Elena Hernández-García Michel Enamorado Christian P Bromley Manuel J Gomez Santiago Zelenay Salvador Iborra Matthew F. Krummel |
| author_facet | Ignacio Melero Ruth Conde-Garrosa David Sancho Santos Mañes Alfonso R Sanchez-Paulete Francisco J Cueto Carlos del Fresno Paola Brandi Alexis J. Combes Elena Hernández-García Michel Enamorado Christian P Bromley Manuel J Gomez Santiago Zelenay Salvador Iborra Matthew F. Krummel |
| author_sort | Ignacio Melero |
| collection | DOAJ |
| description | Background Conventional type 1 dendritic cells (cDC1s) are central to antitumor immunity and their presence in the tumor microenvironment associates with improved outcomes in patients with cancer. DNGR-1 (CLEC9A) is a dead cell-sensing receptor highly restricted to cDC1s. DNGR-1 has been involved in both cross-presentation of dead cell-associated antigens and processes of disease tolerance, but its role in antitumor immunity has not been clarified yet.Methods B16 and MC38 tumor cell lines were inoculated subcutaneously into wild-type (WT) and DNGR-1-deficient mice. To overexpress Flt3L systemically, we performed gene therapy through the hydrodynamic injection of an Flt3L-encoding plasmid. To characterize the immune response, we performed flow cytometry and RNA-Seq of tumor-infiltrating cDC1s.Results Here, we found that cross-presentation of tumor antigens in the steady state was DNGR-1-independent. However, on Flt3L systemic overexpression, tumor growth was delayed in DNGR-1-deficient mice compared with WT mice. Of note, this protection was recapitulated by anti-DNGR-1-blocking antibodies in mice following Flt3L gene therapy. This improved antitumor immunity was associated with Batf3-dependent enhanced accumulation of CD8+ T cells and cDC1s within tumors. Mechanistically, the deficiency in DNGR-1 boosted an Flt3L-induced specific inflammatory gene signature in cDC1s, including Ccl5 expression. Indeed, the increased infiltration of cDC1s within tumors and their protective effect rely on CCL5/CCR5 chemoattraction. Moreover, FLT3LG and CCL5 or CCR5 gene expression signatures correlate with an enhanced cDC1 signature and a favorable overall survival in patients with cancer. Notably, cyclophosphamide elevated serum Flt3L levels and, in combination with the absence of DNGR-1, synergized against tumor growth.Conclusion DNGR-1 limits the accumulation of tumor-infiltrating cDC1s promoted by Flt3L. Thus, DNGR-1 blockade may improve antitumor immunity in tumor therapy settings associated to high Flt3L expression. |
| format | Article |
| id | doaj-art-7174fcff49ec4c968e5c2cd9447b8742 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2021-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-7174fcff49ec4c968e5c2cd9447b87422025-02-09T19:10:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-05-019510.1136/jitc-2020-002054DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cellsIgnacio Melero0Ruth Conde-Garrosa1David Sancho2Santos Mañes3Alfonso R Sanchez-Paulete4Francisco J Cueto5Carlos del Fresno6Paola Brandi7Alexis J. Combes8Elena Hernández-García9Michel Enamorado10Christian P Bromley11Manuel J Gomez12Santiago Zelenay13Salvador Iborra14Matthew F. Krummel15Instituto de Investigación Sanitaria de Navarra, Pamplona, SpainCentro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, SpainImmunobiology Lab, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, SpainDepartment of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin, Madrid, SpainDivision of Immunology and Immunotherapy, Center for Applied Medical Research, University of Navarra, Pamplona, SpainCentro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, SpainHospital la Paz Institute for Health Research, IdiPAZ, Madrid, SpainCentro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, SpainUCSF CoLabs, University of California, San Francisco, California, USADepartment of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid, Madrid, SpainCentro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, SpainCancer Inflammation and Immunity Group, CRUK Manchester Institute, The University of Manchester, Manchester, UKCentro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, SpainCancer Inflammation and Immunity Group, CRUK Manchester Institute, The University of Manchester, Manchester, UKDepartment of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid, Madrid, SpainDepartment of Pathology, University of California, San Francisco, California, USABackground Conventional type 1 dendritic cells (cDC1s) are central to antitumor immunity and their presence in the tumor microenvironment associates with improved outcomes in patients with cancer. DNGR-1 (CLEC9A) is a dead cell-sensing receptor highly restricted to cDC1s. DNGR-1 has been involved in both cross-presentation of dead cell-associated antigens and processes of disease tolerance, but its role in antitumor immunity has not been clarified yet.Methods B16 and MC38 tumor cell lines were inoculated subcutaneously into wild-type (WT) and DNGR-1-deficient mice. To overexpress Flt3L systemically, we performed gene therapy through the hydrodynamic injection of an Flt3L-encoding plasmid. To characterize the immune response, we performed flow cytometry and RNA-Seq of tumor-infiltrating cDC1s.Results Here, we found that cross-presentation of tumor antigens in the steady state was DNGR-1-independent. However, on Flt3L systemic overexpression, tumor growth was delayed in DNGR-1-deficient mice compared with WT mice. Of note, this protection was recapitulated by anti-DNGR-1-blocking antibodies in mice following Flt3L gene therapy. This improved antitumor immunity was associated with Batf3-dependent enhanced accumulation of CD8+ T cells and cDC1s within tumors. Mechanistically, the deficiency in DNGR-1 boosted an Flt3L-induced specific inflammatory gene signature in cDC1s, including Ccl5 expression. Indeed, the increased infiltration of cDC1s within tumors and their protective effect rely on CCL5/CCR5 chemoattraction. Moreover, FLT3LG and CCL5 or CCR5 gene expression signatures correlate with an enhanced cDC1 signature and a favorable overall survival in patients with cancer. Notably, cyclophosphamide elevated serum Flt3L levels and, in combination with the absence of DNGR-1, synergized against tumor growth.Conclusion DNGR-1 limits the accumulation of tumor-infiltrating cDC1s promoted by Flt3L. Thus, DNGR-1 blockade may improve antitumor immunity in tumor therapy settings associated to high Flt3L expression.https://jitc.bmj.com/content/9/5/e002054.full |
| spellingShingle | Ignacio Melero Ruth Conde-Garrosa David Sancho Santos Mañes Alfonso R Sanchez-Paulete Francisco J Cueto Carlos del Fresno Paola Brandi Alexis J. Combes Elena Hernández-García Michel Enamorado Christian P Bromley Manuel J Gomez Santiago Zelenay Salvador Iborra Matthew F. Krummel DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells Journal for ImmunoTherapy of Cancer |
| title | DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells |
| title_full | DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells |
| title_fullStr | DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells |
| title_full_unstemmed | DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells |
| title_short | DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells |
| title_sort | dngr 1 limits flt3l mediated antitumor immunity by restraining tumor infiltrating type i conventional dendritic cells |
| url | https://jitc.bmj.com/content/9/5/e002054.full |
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