Intratumoral delivery of FLT3L with CXCR3/CCR5 ligands promotes XCR1+ cDC1 infiltration and activates anti-tumor immunity
Abstract
Abstract 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.
Article Details
Authors (32)
Louise Gorline
Fillipe Luiz Rosa do Carmo
Pierre Bourdely
Jérémie Bornères
Nathan Vaudiau
Aurélie Semervil
Mathias Vetillard
Aboubacar Sidiki K Coulibaly
Natacha Jugniot
Agathe Ok
Mathilde Bausart
Oriane Fiquet
Marine Andrade
Dicken Fardol
Ikrame Haddar
Zeina Abou Nader
Judith Weber
Hannah Theobald
Matthieu Collin
Joseph Calmette
Giorgio Anselmi
Flavia Fico
Florent Ginhoux
Laleh Majlessi
Emmanuel L. Gautier
Loredana Saveanu
Julie Helft
Marc Dalod
Mathilde Dusseaux
James P. Di Santo
Stéphanie Hugues
Pierre Guermonprez