[en] Combining immunogenic cell death-inducing chemotherapies and PD-1 blockade can generate remarkable tumor responses. It is now well established that TGF-β1 signaling is a major component of treatment resistance and contributes to the cancer-related immunosuppressive microenvironment. However, whether TGF-β1 remains an obstacle to immune checkpoint inhibitor efficacy when immunotherapy is combined with chemotherapy is still to be determined. Several syngeneic murine models were used to investigate the role of TGF-β1 neutralization on the combinations of immunogenic chemotherapy (FOLFOX: 5-fluorouracil and oxaliplatin) and anti-PD-1. Cancer-associated fibroblasts (CAF) and immune cells were isolated from CT26 and PancOH7 tumor-bearing mice treated with FOLFOX, anti-PD-1 ± anti-TGF-β1 for bulk and single cell RNA sequencing and characterization. We showed that TGF-β1 neutralization promotes the therapeutic efficacy of FOLFOX and anti-PD-1 combination and induces the recruitment of antigen-specific CD8+ T cells into the tumor. TGF-β1 neutralization is required in addition to chemo-immunotherapy to promote inflammatory CAF infiltration, a chemokine production switch in CAF leading to decreased CXCL14 and increased CXCL9/10 production and subsequent antigen-specific T cell recruitment. The immune-suppressive effect of TGF-β1 involves an epigenetic mechanism with chromatin remodeling of CXCL9 and CXCL10 promoters within CAF DNA in a G9a and EZH2-dependent fashion. Our results strengthen the role of TGF-β1 in the organization of a tumor microenvironment enriched in myofibroblasts where chromatin remodeling prevents CXCL9/10 production and limits the efficacy of chemo-immunotherapy.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Vienot, Angélique; Department of Medical Oncology, University Hospital of Besançon, F-25000 Besançon, France ; INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France ; Clinical Investigational Center, CIC-1431, F-25000 Besançon, France
Pallandre, Jean-René; INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France
Renaude, Elodie ; Université de Liège - ULiège > GIGA > GIGA Cancer - Cancer Signaling ; INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France
Viot, Julien; Department of Medical Oncology, University Hospital of Besançon, F-25000 Besançon, France ; INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France
Bouard, Adeline; INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France ; ITAC platform, University of Bourgogne Franche-Comté, F-25000 Besançon, France
Spehner, Laurie; INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France
Kroemer, Marie; INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France ; ITAC platform, University of Bourgogne Franche-Comté, F-25000 Besançon, France
Abdeljaoued, Syrine; INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France
van der Woning, Bas; Argenx, 9052 Zwijnaarde, Belgium
de Haard, Hans; Argenx, 9052 Zwijnaarde, Belgium
Loyon, Romain; INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France
Hervouet, Eric; INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France ; EPIgenetics and GENe EXPression Technical Platform (EPIGENExp), University of Bourgogne Franche-Comté, F-25000 Besançon, France
Peixoto, Paul ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases ; INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France ; EPIgenetics and GENe EXPression Technical Platform (EPIGENExp), University of Bourgogne Franche-Comté, F-25000 Besançon, France
Borg, Christophe; Department of Medical Oncology, University Hospital of Besançon, F-25000 Besançon, France ; INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France ; Clinical Investigational Center, CIC-1431, F-25000 Besançon, France ; ITAC platform, University of Bourgogne Franche-Comté, F-25000 Besançon, France
This work was supported by grants from the Ligue contre le cancer du grand Est, the Cancéropôle Est, and from Région Bourgogne Franche-Comté. We thank the Institute of Genetics and Molecular and Cellular Biology (Ilkirch, France) for technical assistance.CB declares research grant from Roche, Bayer and advisory board for MSD, Sanofi, Bayer. All other authors report no conflict of interest.The author(s) reported there is no funding associated with the work featured in this article. This work was supported by grants from the Ligue contre le cancer du grand Est, the Cancéropôle Est, and from Région Bourgogne Franche-Comté. We thank the Institute of Genetics and Molecular and Cellular Biology (Ilkirch, France) for technical assistance.
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