TGF-β and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies
TGF-β and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies
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DOI：
10.1172/jci.insight.85974
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发表时间：
2016-06-16
期刊：
影响因子：
8
通讯作者：
Klatzmann, David
中科院分区：
文献类型：
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作者：
Courau, Tristan;Nehar-Belaid, Djamel;Klatzmann, David
肿瘤标志物是一种早期免疫耐受性肿瘤环境，可阻止有效的抗肿瘤免疫应答。使用肿瘤组织的转录组学，我们确定了与耐受印记相容的VEGF和TGF-β途径的早期上调。肿瘤细胞中VEGF或TGF-β的沉默诱导肿瘤组织中免疫相关转录组特征的早期和多效性调节。这些对于两种沉默的肿瘤都是令人惊讶的相似的，并且与对TcB的常见下游效应有关。VEGF或TGF-β的沉默导致肿瘤生长显著延迟，与肿瘤浸润中的T细胞和髓源性抑制细胞减少和效应T细胞活化增加相关。引人注目的是，TGF-β和VEGF的共沉默导致显著的自发肿瘤根除率，并且它们各自的抑制药物的组合是协同的。VEGF和/或TGF-β沉默也恢复了肿瘤对肿瘤特异性细胞疗法的敏感性，并显著改善了抗PD-1/抗CTLA-4治疗的疗效。因此，TGF-β和VEGF协同控制肿瘤的耐受环境，并且是改善癌症免疫疗法的靶点。
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.