TGF-β and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies
Tristan Courau, Djamel Nehar-Belaid, Laura Florez, Béatrice Levacher, Thomas Vazquez, Faustine Brimaud, Bertrand Bellier, David Klatzmann
Tristan Courau, Djamel Nehar-Belaid, Laura Florez, Béatrice Levacher, Thomas Vazquez, Faustine Brimaud, Bertrand Bellier, David Klatzmann
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Research Article Immunology Oncology

TGF-β and 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

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

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Figure 7

Tumor-derived VEGF and TGF-β contribute to the onset of dominant tolerance and are therefore valuable targets for combination therapies.

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Tumor-derived VEGF and TGF-β contribute to the onset of dominant toleran...
(A–D) Kaplan-Meier survival curves of B16gp- (A), B16gp-shVEGF– (B), B16gp-shTGF-β– (C), or B16gp-shTGF-β/shVEGF– (D) bearing WT C57BL/6 mice injected s.c. with recombinant lymphocytic choriomeningitis virus envelope glycoprotein (gp) model antigen–expressing tumors at day 0 and i.v. with PBS or with 4 × 106 gp-specific activated/memory effector T cells (amTeffs) from immunized mice at day 0 or day 4; n = 5 mice per group. Survival rate was significantly higher in B16gp-bearing mice when amTeffs were injected at day 0 compared with day 4 (log-rank test, P = 0.0324), whereas it was not in response to the other tumors. (E) Kinetics and (F) Kaplan-Meier survival curves of parental B16 tumor–bearing WT C57BL/6 mice treated or not with sunitinib during 2 weeks and/or SB431542 at days 3, 6, and 9; n = 5 per group. (G–J) Kaplan-Meier survival curves of B16- (G), B16-shVEGF– (H), B16-shTGF-β– (I), or B16-shTGF-β/shVEGF– (J) bearing WT C57BL/6 mice treated or not at days 3, 6, and 9 with a cocktail of 100 μg anti–CTLA-4 and 250 μg anti–PD-1 antibodies; n = 11 mice per group in 2 independent experiments. Survival rate was significantly higher in the B16-shVEGF–bearing (P = 0.048) and B16-shTGF-β/shVEGF–bearing (log-rank test, P = 0.0041) treated groups compared with the B16-bearing treated group. Statistical significance of the survival curves was analyzed by using the log-rank test (*P < 0.05; **P < 0.005).