Intratumoral delivery of FLT3L with CXCR3/CCR5 ligands promotes XCR1+ cDC1 infiltration and activates anti-tumor immunity
Tumor infiltration by XCR1⁺ conventional dendritic cells (cDC1) correlates strongly with favorable prognosis and improved responses to immunotherapy. Yet, tumor-driven immunosuppressive programs restrict efficient cDC1 recruitment, highlighting the need for strategies to increase cDC1 access to the tumor microenvironment. Here, we establish a proof-of-concept cell-based immunotherapy that enhances the infiltration of circulating cDC1 progenitors and supports their local expansion. Intratumoral engraftment of autologous mesenchymal stromal cells engineered to express membrane bound FLT3L promotes cDC1 recruitment when combined with poly(I:C). We identify poly(I:C)-induced CXCL9 and CCL5 as essential chemokines controlling intratumoral cDC1 infiltration. Stromal cell-mediated local delivery of FLT3L together with CXCL9 and CCL5 is sufficient to enhance cDC1 infiltration in mice or humanized mice settings. Finally, this approach activates antitumor immunity and partially overcomes resistance to immune checkpoint blockade. Collectively, our data support the therapeutic potential of expanding intratumoral cDC1s through local and sustained delivery of FLT3L, CXCL9, and CCL5.
Authors
- Hannah Theobald (ORCID: https://orcid.org/0000-0003-4580-5542)
- Zeina Abou Nader (ORCID: https://orcid.org/0009-0008-6264-2574)
- Emmanuel L. Gautier (ORCID: https://orcid.org/0000-0003-2976-7566)
- Mathilde Bausart (ORCID: https://orcid.org/0000-0003-4580-5542)
- Julie Helft (ORCID: https://orcid.org/0000-0002-2733-1972)
- Dicken Fardol
- Matthieu Collin (ORCID: https://orcid.org/0000-0002-4247-3645)
- Pierre Bourdely (ORCID: https://orcid.org/0000-0002-4162-1490)
- Pierre Guermonprez (ORCID: https://orcid.org/0000-0001-5621-2262)
- Mathias Vétillard (ORCID: https://orcid.org/0000-0001-5503-4900)
- Nathan Vaudiau (ORCID: https://orcid.org/0000-0001-9586-8467)
- Loredana Saveanu (ORCID: https://orcid.org/0000-0003-3138-7968)
- Joseph Calmette
- Giorgio Anselmi (ORCID: https://orcid.org/0000-0002-8870-3354)
- James P. Di Santo (ORCID: https://orcid.org/0000-0002-7146-1862)
- Aboubacar Sidiki K. Coulibaly
- Judith Weber
- Louise Gorline (ORCID: https://orcid.org/0009-0008-8499-9603)
- Aurélie Semervil
- Oriane Fiquet
- Florent Ginhoux
- Jérémie Bornères
- Ikrame Haddar
- Laleh Majlessi
- Mathilde Dusseaux
- Fillipe Luiz Rosa do Carmo
- Marc Dalod
- Flavia Fico
- Natacha Jugniot
- Marine Andrade
- Agathe Ok
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Institut Pasteur (FR)
- Délégation Paris 7 (FR)
- Université Paris Cité (FR)
- Université Paris-Saclay (FR)
- Institut Gustave Roussy (FR)
- Sorbonne Université (FR)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Nutrition et obésité : approches systémiques (FR)
- Inserm Transfert (FR)
- Institut Cochin (FR)
- Centre d’Immunologie de Marseille-Luminy (FR)
- International Centre for Genetic Engineering and Biotechnology (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-30
- DOI
- https://doi.org/10.1038/s41467-025-68018-3
- Citations
- 1
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.80