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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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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 <jats:italic>Flt3L<\/jats:italic> gene therapy. This improved antitumor immunity was associated with <jats:italic>Batf3<\/jats:italic>-dependent enhanced accumulation of CD8<jats:sup>+<\/jats:sup> T cells and cDC1s within tumors. Mechanistically, the deficiency in DNGR-1 boosted an Flt3L-induced specific inflammatory gene signature in cDC1s, including <jats:italic>Ccl5<\/jats:italic> expression. Indeed, the increased infiltration of cDC1s within tumors and their protective effect rely on CCL5\/CCR5 chemoattraction. Moreover, <jats:italic>FLT3LG<\/jats:italic> and <jats:italic>CCL5<\/jats:italic> or <jats:italic>CCR5<\/jats:italic> 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2020-002054","type":"journal-article","created":{"date-parts":[[2021,5,12]],"date-time":"2021-05-12T13:11:49Z","timestamp":1620825109000},"page":"e002054","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":44,"title":["DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells"],"prefix":"10.1136","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7457-9583","authenticated-orcid":false,"given":"Francisco J","family":"Cueto","sequence":"first","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, 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