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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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Categories: 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 6

VEGF or TGF-β silencing concomitantly induces similar and partially nonoverlapping effects on antitumor immune response that correlate with defects in Treg response, and their co-silencing leads to T cell–dependent spontaneous rejection of B16 tumors.

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VEGF or TGF-β silencing concomitantly induces similar and partially nono...
(A) Venn representations of the comparison between significantly modulated signature numbers (in black) measured by microarray analyses in three conditions (B16 vs. B16-PC61 in blue, B16 vs. B16-shVEGF in orange, and B16 vs. B16-shTGF-β in purple), 4 days (left panel) or 14 days (right panel) after tumor inoculation. Numbers of immune-related signatures are represented in red. (B) Cytoscape representation of signatures differently regulated in B16-shVEGF and B16-shTGF-β tumors, measured by microarray. (C and D) Kaplan-Meier survival curves of (C) CD3ε-KO and (D) C57BL/6 WT mice inoculated with the listed tumors; n = 10 mice per group in 2 independent experiments. Statistical significance of the survival curves was analyzed by using the log-rank test (**P < 0.005, ***P < 0.001).
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