DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells
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.
Affiliation
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.Issue Date
2021
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Show full item recordAbstract
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 CancerDOI
10.1136/jitc-2020-002054PubMed ID
33980589Additional Links
https://dx.doi.org/10.1136/jitc-2020-002054Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1136/jitc-2020-002054
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