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

被引：113

作者：

Courau, Tristan ^{[1
,2
]}

Nehar-Belaid, Djamel ^{[1
,2
]}

Florez, Laura ^{[1
,2
]}

Levacher, Beatrice ^{[1
,2
]}

Vazquez, Thomas ^{[1
,2
]}

Brimaud, Faustine ^{[1
,2
,3
]}

Bellier, Bertrand ^{[1
,2
]}

Klatzmann, David ^{[1
,2
,3
]}

机构：

[1] Sorbonne Univ, UPMC Univ Paris, Paris, France

[2] INSERM UMR S 959, Paris, France

[3] Grp Hosp Pitie Salpetriere, AP HP, Dept Biotherapies, Clin Invest Ctr Biotherapy & Inflamat Immunopatho, F-75013 Paris, France

来源：

JCI INSIGHT | 2016年 / 1卷 / 09期

基金：

欧洲研究理事会;

关键词：

REGULATORY T-CELLS; ENDOTHELIAL GROWTH-FACTOR; DENDRITIC CELLS; IMMUNE CELLS; ANTITUMOR; BLOCKADE; EXPRESSION; MATURATION; MICROENVIRONMENT; COMBINATION;

D O I：

10.1172/jci.insight.85974

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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-beta pathways compatible with tolerance imprinting. Silencing of VEGF or TGF-beta 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-beta 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-beta and VEGF led to a substantial spontaneous tumor eradication rate and the combination of their respective inhibitory drugs was synergistic. VEGF and/or TGF-beta 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-beta and VEGF cooperatively control the tolerant environment of tumors and are targets for improved cancer immunotherapies.

引用

页数：16

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