title: TGF-βand VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies.
abstract: Tregs imprint an early immunotolerant tumor environment that prevents effective antitumor immune responses. Using transcriptomics of tumor tissues, we identified early upregulation of VEGF and TGF-β pathways compatible with tolerance imprinting. Silencing of VEGF or TGF-β in tumor cells induced early and pleiotropic modulation of immune-related transcriptome signatures in tumor tissues. These were surprisingly similar for both silenced tumors and related to common downstream effects on Tregs. Silencing of VEGF or TGF-β resulted in dramatically delayed tumor growth, associated with decreased Tregs and myeloid-derived suppressor cells and increased effector T cell activation in tumor infiltrates. Strikingly, co-silencing of TGF-β and VEGF led to a substantial spontaneous tumor eradication rate and the combination of their respective inhibitory drugs was synergistic. VEGF and/or TGF-β silencing also restored tumor sensitivity to tumor-specific cell therapies and markedly improved the efficacy of anti-PD-1/anti-CTLA-4 treatment. Thus, TGF-β and VEGF cooperatively control the tolerant environment of tumors and are targets for improved cancer immunotherapies.
authors.affiliation: Sorbonne Universités, UPMC University of Paris, Paris, France.|INSERM UMR_S 959, Paris, France.
authors.forename: Tristan
authors.initials: T
authors.lastname: Courau
authors.affiliation: Sorbonne Universités, UPMC University of Paris, Paris, France.|INSERM UMR_S 959, Paris, France.
authors.forename: Djamel
authors.initials: D
authors.lastname: Nehar-Belaid
authors.affiliation: Sorbonne Universités, UPMC University of Paris, Paris, France.|INSERM UMR_S 959, Paris, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Florez
authors.affiliation: Sorbonne Universités, UPMC University of Paris, Paris, France.|INSERM UMR_S 959, Paris, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Levacher
authors.affiliation: Sorbonne Universités, UPMC University of Paris, Paris, France.|INSERM UMR_S 959, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vazquez
authors.affiliation: Sorbonne Universités, UPMC University of Paris, Paris, France.|INSERM UMR_S 959, Paris, France.|AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Biotherapies, Clinical Investigation Center in Biotherapy and Inflamation-Immunopathology-Biotherapy Department (DHU I2B), F-75013, Paris, France.
authors.forename: Faustine
authors.initials: F
authors.lastname: Brimaud
authors.affiliation: Sorbonne Universités, UPMC University of Paris, Paris, France.|INSERM UMR_S 959, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Bellier
authors.affiliation: Sorbonne Universités, UPMC University of Paris, Paris, France.|INSERM UMR_S 959, Paris, France.|AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Biotherapies, Clinical Investigation Center in Biotherapy and Inflamation-Immunopathology-Biotherapy Department (DHU I2B), F-75013, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Klatzmann
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D020868:Gene Silencing; D007108:Immune Tolerance; D007167:Immunotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A