Intratumoral delivery of FLT3L with CXCR3/CCR5 ligands promotes XCR1+ cDC1 infiltration and activates anti-tumor immunity
(1) Gorline L (2) do Carmo FLR (3) Bourdely P (4) Bornres J (5) Vaudiau N (6) Semervil A (7) Vetillard M (8) Coulibaly ASK (9) Jugniot N (10) Ok A (11) Bausart M (12) Fiquet O (13) Andrade M (14) Fardol D (15) Haddar I (16) Abou Nader Z (17) Weber J (18) Theobald H (19) Collin M (20) Calmette J (21) Anselmi G (22) Fico F (23) Ginhoux F (24) Majlessi L (25) Gautier EL (26) Saveanu L (27) Helft J (28) Dalod M (29) Dusseaux M (30) Di Santo JP (31) Hugues S (32) Guermonprez P
To overcome active inhibition of cDC1 recruitment to tumors, Gorline and Rosa do Carmo et al. showed that mesenchymal stromal cells (MSC), engineered to express the membrane-bound form of FLT3L and delivered intratumorally, required pIC activation of CCL5 and CXCL9 to enhance the migration of DCs into tumors and to draining lymph nodes. Antigen cross-presentation, infiltration of T and NK cells, T cell activation, and synergy with ICB were all increased. Expression of the chemokines in the FLT3L-engineered MSC replaced the need for pIC, replicating the benefit. Engineered MSCs expressing the human factors enhanced DC engraftment in a humanized mouse model.
Contributed by Ed Fritsch
(1) Gorline L (2) do Carmo FLR (3) Bourdely P (4) Bornres J (5) Vaudiau N (6) Semervil A (7) Vetillard M (8) Coulibaly ASK (9) Jugniot N (10) Ok A (11) Bausart M (12) Fiquet O (13) Andrade M (14) Fardol D (15) Haddar I (16) Abou Nader Z (17) Weber J (18) Theobald H (19) Collin M (20) Calmette J (21) Anselmi G (22) Fico F (23) Ginhoux F (24) Majlessi L (25) Gautier EL (26) Saveanu L (27) Helft J (28) Dalod M (29) Dusseaux M (30) Di Santo JP (31) Hugues S (32) Guermonprez P
To overcome active inhibition of cDC1 recruitment to tumors, Gorline and Rosa do Carmo et al. showed that mesenchymal stromal cells (MSC), engineered to express the membrane-bound form of FLT3L and delivered intratumorally, required pIC activation of CCL5 and CXCL9 to enhance the migration of DCs into tumors and to draining lymph nodes. Antigen cross-presentation, infiltration of T and NK cells, T cell activation, and synergy with ICB were all increased. Expression of the chemokines in the FLT3L-engineered MSC replaced the need for pIC, replicating the benefit. Engineered MSCs expressing the human factors enhanced DC engraftment in a humanized mouse model.
Contributed by Ed Fritsch
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.
Author Info:
(1) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, Universit de Paris Cit, Paris, France. CNRS UMR3738, Developmental Biology and Stem Cells
, Institut Pasteur, Universit de Paris Cit, Paris, France. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. (2) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, Universit de Paris Cit, Paris, France. CNRS UMR3738, Developmental Biology and Stem Cells, Institut Pasteur, Universit de Paris Cit, Paris, France. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. (3) Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. INSERM UMR 1016, CNRS UMR 8104, Institut Cochin, Universit Paris Cit, Paris, France. (4) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, Universit de Paris Cit, Paris, France. CNRS UMR3738, Developmental Biology and Stem Cells, Institut Pasteur, Universit de Paris Cit, Paris, France. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. (5) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, Universit de Paris Cit, Paris, France. CNRS UMR3738, Developmental Biology and Stem Cells, Institut Pasteur, Universit de Paris Cit, Paris, France. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. (6) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, Universit de Paris Cit, Paris, France. CNRS UMR3738, Developmental Biology and Stem Cells, Institut Pasteur, Universit de Paris Cit, Paris, France. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. INSERM UMR 1016, CNRS UMR 8104, Institut Cochin, Universit Paris Cit, Paris, France. (7) Bichat Medical School, INSERM UMR1149, CNRS EMR8252, Universit Paris Cit, Paris, France. (8) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, Universit de Paris Cit, Paris, France. CNRS UMR3738, Developmental Biology and Stem Cells, Institut Pasteur, Universit de Paris Cit, Paris, France. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. (9) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, Universit de Paris Cit, Paris, France. CNRS UMR3738, Developmental Biology and Stem Cells, Institut Pasteur, Universit de Paris Cit, Paris, France. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. (10) Bichat Medical School, INSERM UMR1149, CNRS EMR8252, Universit Paris Cit, Paris, France. (11) Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland. (12) Human Disease Models Core Facility, Institut Pasteur, Universit Paris Cit, Paris, France. (13) Human Disease Models Core Facility, Institut Pasteur, Universit Paris Cit, Paris, France. (14) Nutrition and Obesity: Systemic Approaches, Inserm, Sorbonne University, Paris, France. (15) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, Universit de Paris Cit, Paris, France. CNRS UMR3738, Developmental Biology and Stem Cells, Institut Pasteur, Universit de Paris Cit, Paris, France. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. (16) INSERM UMR 1016, CNRS UMR 8104, Institut Cochin, Universit Paris Cit, Paris, France. (17) INSERM UMR 1016, CNRS UMR 8104, Institut Cochin, Universit Paris Cit, Paris, France. (18) Inserm U1015, Institut Gustave Roussy, Universit Paris-Saclay, Villejuif, France. (19) Inserm Transfert, Paris, France. (20) Inserm Transfert, Paris, France. (21) Deparment of Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy. (22) Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland. (23) Inserm U1015, Institut Gustave Roussy, Universit Paris-Saclay, Villejuif, France. (24) Virology Department, Pasteur-TheraVectys Joint Laboratory, Institut Pasteur, Universit Paris Cit, Paris, France. (25) Nutrition and Obesity: Systemic Approaches, Inserm, Sorbonne University, Paris, France. (26) Bichat Medical School, INSERM UMR1149, CNRS EMR8252, Universit Paris Cit, Paris, France. (27) INSERM UMR 1016, CNRS UMR 8104, Institut Cochin, Universit Paris Cit, Paris, France. (28) Centre d'Immunologie de Marseille-Luminy, CIML, CNRS, INSERM, Aix Marseille Universit, Marseille, France. (29) Human Disease Models Core Facility, Institut Pasteur, Universit Paris Cit, Paris, France. (30) Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. Immunology Department, Immunit Inne, Institut Pasteur, Paris, France. (31) Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland. (32) Dendritic Cells and Adaptive Immunity Unit, Immunology Department, Institut Pasteur, Universit de Paris Cit, Paris, France. pierre.guermonprez@pasteur.fr. CNRS UMR3738, Developmental Biology and Stem Cells, Institut Pasteur, Universit de Paris Cit, Paris, France. pierre.guermonprez@pasteur.fr. Centre for Vaccine and Immunotherapy, Institut Pasteur, Paris, France. pierre.guermonprez@pasteur.fr.
