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 i...
| Autores: | , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/115225 |
| Acceso en línea: | https://hdl.handle.net/10171/115225 |
| Access Level: | acceso abierto |
| Palabra clave: | CCL5 Cancer DNGR-1/Clec9a Flt3L cDC1 Dendritic cells Immunomodulation Immunotherapy Maraviroc |
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DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cellsCueto, F.J. (Francisco J.)|||/items/3abfb0a7-6757-471d-a391-6b9ea52605b8Fresno, C. (Carlos) del|||/items/b6d90b8c-8a41-4d0a-a5f7-03bd98558bfbBrandi, P. (Paola)|||/items/cef308d6-748c-40f4-a6d3-3bf336eccd92Combes, A.J. (Alexis J.)|||/items/f16b03a7-7d3d-4f5a-9282-cf2673d3875bHernández-García, E. (Elena)|||/items/7ef9b77a-cc2a-4630-b8e0-554145356dddSanchez-Paulete, A.R. (Alfonso R.)|||/items/b301b8f2-0399-464a-a885-b9b56047cfd7Enamorado, M. (Michel)|||/items/48c01050-fcba-4324-a207-9d4aef7fcfd4Bromley, C.P. (Christian P.)|||/items/d97259dd-842b-4538-ab18-9e2ac00d7477Gomez, J.M. (José Manuel)|||/items/205aa60f-c530-4059-a819-7504c9132e06Conde-Garrosa, R. (Ruth)|||/items/e4f6d493-6b38-46e4-a316-975756399740Mañes, S. (Santos)|||/items/43ed1aed-3c29-46e5-acc0-db1d566e27c6Zelenay, S. (Santiago)|||/items/7a4b9804-de1a-40dc-83d7-7b73389b8b88Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4eIborra, S. (Salvador)|||/items/c310442f-deb2-4420-9e85-f1c2fdd8f6c2Krummel, M.F. (Matthew F.)|||/items/69bd4e03-4606-40f4-a0a1-32cba42b4bd4Sancho, D. (David)|||/items/c3d4d82f-7d28-41c4-83f9-6220a560707fCCL5CancerDNGR-1/Clec9aFlt3LcDC1Dendritic cellsImmunomodulationImmunotherapyMaravirocBackground: 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.BMJDadun. Depósito Académico Digital Universidad de Navarra20212021-01-0120212021-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/115225reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/1152252026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells |
| title |
DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells |
| spellingShingle |
DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells Cueto, F.J. (Francisco J.)|||/items/3abfb0a7-6757-471d-a391-6b9ea52605b8 CCL5 Cancer DNGR-1/Clec9a Flt3L cDC1 Dendritic cells Immunomodulation Immunotherapy Maraviroc |
| title_short |
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_sort |
DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells |
| dc.creator.none.fl_str_mv |
Cueto, F.J. (Francisco J.)|||/items/3abfb0a7-6757-471d-a391-6b9ea52605b8 Fresno, C. (Carlos) del|||/items/b6d90b8c-8a41-4d0a-a5f7-03bd98558bfb Brandi, P. (Paola)|||/items/cef308d6-748c-40f4-a6d3-3bf336eccd92 Combes, A.J. (Alexis J.)|||/items/f16b03a7-7d3d-4f5a-9282-cf2673d3875b Hernández-García, E. (Elena)|||/items/7ef9b77a-cc2a-4630-b8e0-554145356ddd Sanchez-Paulete, A.R. (Alfonso R.)|||/items/b301b8f2-0399-464a-a885-b9b56047cfd7 Enamorado, M. (Michel)|||/items/48c01050-fcba-4324-a207-9d4aef7fcfd4 Bromley, C.P. (Christian P.)|||/items/d97259dd-842b-4538-ab18-9e2ac00d7477 Gomez, J.M. (José Manuel)|||/items/205aa60f-c530-4059-a819-7504c9132e06 Conde-Garrosa, R. (Ruth)|||/items/e4f6d493-6b38-46e4-a316-975756399740 Mañes, S. (Santos)|||/items/43ed1aed-3c29-46e5-acc0-db1d566e27c6 Zelenay, S. (Santiago)|||/items/7a4b9804-de1a-40dc-83d7-7b73389b8b88 Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4e Iborra, S. (Salvador)|||/items/c310442f-deb2-4420-9e85-f1c2fdd8f6c2 Krummel, M.F. (Matthew F.)|||/items/69bd4e03-4606-40f4-a0a1-32cba42b4bd4 Sancho, D. (David)|||/items/c3d4d82f-7d28-41c4-83f9-6220a560707f |
| author |
Cueto, F.J. (Francisco J.)|||/items/3abfb0a7-6757-471d-a391-6b9ea52605b8 |
| author_facet |
Cueto, F.J. (Francisco J.)|||/items/3abfb0a7-6757-471d-a391-6b9ea52605b8 Fresno, C. (Carlos) del|||/items/b6d90b8c-8a41-4d0a-a5f7-03bd98558bfb Brandi, P. (Paola)|||/items/cef308d6-748c-40f4-a6d3-3bf336eccd92 Combes, A.J. (Alexis J.)|||/items/f16b03a7-7d3d-4f5a-9282-cf2673d3875b Hernández-García, E. (Elena)|||/items/7ef9b77a-cc2a-4630-b8e0-554145356ddd Sanchez-Paulete, A.R. (Alfonso R.)|||/items/b301b8f2-0399-464a-a885-b9b56047cfd7 Enamorado, M. (Michel)|||/items/48c01050-fcba-4324-a207-9d4aef7fcfd4 Bromley, C.P. (Christian P.)|||/items/d97259dd-842b-4538-ab18-9e2ac00d7477 Gomez, J.M. (José Manuel)|||/items/205aa60f-c530-4059-a819-7504c9132e06 Conde-Garrosa, R. (Ruth)|||/items/e4f6d493-6b38-46e4-a316-975756399740 Mañes, S. (Santos)|||/items/43ed1aed-3c29-46e5-acc0-db1d566e27c6 Zelenay, S. (Santiago)|||/items/7a4b9804-de1a-40dc-83d7-7b73389b8b88 Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4e Iborra, S. (Salvador)|||/items/c310442f-deb2-4420-9e85-f1c2fdd8f6c2 Krummel, M.F. (Matthew F.)|||/items/69bd4e03-4606-40f4-a0a1-32cba42b4bd4 Sancho, D. (David)|||/items/c3d4d82f-7d28-41c4-83f9-6220a560707f |
| author_role |
author |
| author2 |
Fresno, C. (Carlos) del|||/items/b6d90b8c-8a41-4d0a-a5f7-03bd98558bfb Brandi, P. (Paola)|||/items/cef308d6-748c-40f4-a6d3-3bf336eccd92 Combes, A.J. (Alexis J.)|||/items/f16b03a7-7d3d-4f5a-9282-cf2673d3875b Hernández-García, E. (Elena)|||/items/7ef9b77a-cc2a-4630-b8e0-554145356ddd Sanchez-Paulete, A.R. (Alfonso R.)|||/items/b301b8f2-0399-464a-a885-b9b56047cfd7 Enamorado, M. (Michel)|||/items/48c01050-fcba-4324-a207-9d4aef7fcfd4 Bromley, C.P. (Christian P.)|||/items/d97259dd-842b-4538-ab18-9e2ac00d7477 Gomez, J.M. (José Manuel)|||/items/205aa60f-c530-4059-a819-7504c9132e06 Conde-Garrosa, R. (Ruth)|||/items/e4f6d493-6b38-46e4-a316-975756399740 Mañes, S. (Santos)|||/items/43ed1aed-3c29-46e5-acc0-db1d566e27c6 Zelenay, S. (Santiago)|||/items/7a4b9804-de1a-40dc-83d7-7b73389b8b88 Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4e Iborra, S. (Salvador)|||/items/c310442f-deb2-4420-9e85-f1c2fdd8f6c2 Krummel, M.F. (Matthew F.)|||/items/69bd4e03-4606-40f4-a0a1-32cba42b4bd4 Sancho, D. (David)|||/items/c3d4d82f-7d28-41c4-83f9-6220a560707f |
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author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Dadun. Depósito Académico Digital Universidad de Navarra |
| dc.subject.none.fl_str_mv |
CCL5 Cancer DNGR-1/Clec9a Flt3L cDC1 Dendritic cells Immunomodulation Immunotherapy Maraviroc |
| topic |
CCL5 Cancer DNGR-1/Clec9a Flt3L cDC1 Dendritic cells Immunomodulation Immunotherapy Maraviroc |
| 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. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 2021-01-01 2021 2021-01-01 |
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journal article http://purl.org/coar/resource_type/c_6501 |
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info:eu-repo/semantics/article |
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article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10171/115225 |
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https://hdl.handle.net/10171/115225 |
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Inglés eng |
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Inglés |
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eng |
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open access http://purl.org/coar/access_right/c_abf2 |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 |
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openAccess |
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application/pdf |
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BMJ |
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BMJ |
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reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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