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    DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells

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    Authors
    Cueto, F. J.
    Del Fresno, C.
    Brandi, P.
    Combes, A. J.
    Hernández-García, E.
    Sánchez-Paulete, A. R.
    Enamorado, M.
    Bromley, Christian P
    Gomez, M. J.
    Conde-Garrosa, R.
    Mañes, S.
    Zelenay, Santiago
    Melero, I.
    Iborra, S.
    Krummel, M
    F.Sancho, D.
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    Affiliation
    Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
    Issue Date
    2021
    
    Metadata
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    Abstract
    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.
    Citation
    Cueto FJ, del Fresno C, Brandi P, Combes AJ, Hernández-García E, Sánchez-Paulete AR, et al. DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells. J Immunother Cancer. 2021 May;9(5):e002054. 
    Journal
    Journal for Immunotherapy of Cancer
    URI
    http://hdl.handle.net/10541/624124
    DOI
    10.1136/jitc-2020-002054
    PubMed ID
    33980589
    Additional Links
    https://dx.doi.org/10.1136/jitc-2020-002054
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1136/jitc-2020-002054
    Scopus Count
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