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TGF-β and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies
Tristan Courau, … , Bertrand Bellier, David Klatzmann
Tristan Courau, … , Bertrand Bellier, David Klatzmann
Published June 16, 2016
Citation Information: JCI Insight. 2016;1(9):e85974. https://doi.org/10.1172/jci.insight.85974.
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Research Article Immunology Oncology

TGF-β and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies

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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

Tristan Courau, Djamel Nehar-Belaid, Laura Florez, Béatrice Levacher, Thomas Vazquez, Faustine Brimaud, Bertrand Bellier, David Klatzmann

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Figure 1

VEGF or TGF-β silencing in B16 tumors reverses the early and pleiotropic inhibition of immune signature networks at the tumor sites.

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VEGF or TGF-β silencing in B16 tumors reverses the early and pleiotropic...
Microarray analyses of WT or silenced B16 tumor tissues obtained at day 4 after inoculation in C57BL/6 WT mice (n = 6 per group). Enrichments of Gene Ontology–compiled signatures were tested using gene set enrichment analysis and represented using Cytoscape software. (A and B) Cytoscape representations of significantly enriched signatures in (A) B16-shVEGF or (B) B16-shTGF-β tumors as compared with B16 tumors. Each signature is represented by a node of size proportional to the number of genes composing it and color indicates down- (green) or upregulation (red). Networks of related signatures are edged and annotated for their main functions (modules). The immune-related networks are shaded in red.

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