Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation.
Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation.
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DOI：
10.1126/scitranslmed.aak9679
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发表时间：
2017-04-12
影响因子：
17.1
通讯作者：
Bergers G
中科院分区：
文献类型：
--
作者：
Allen E;Jabouille A;Rivera LB;Lodewijckx I;Missiaen R;Steri V;Feyen K;Tawney J;Hanahan D;Michael IP;Bergers G
VEGF（血管内皮生长因子）/VEGFR 2（血管内皮生长因子受体2）的抑制剂常用于临床，但它们的有益效果仅在一部分患者中观察到，并且受到诱导不同复发机制的限制。我们描述了在抗血管生成治疗期间适应性免疫抑制途径的上调，通过该途径，PD-L1（程序性细胞死亡配体1），负性免疫检查点调节剂PD-1（程序性细胞死亡蛋白1）的配体，在难治性胰腺，乳腺和脑肿瘤小鼠模型中的不同瘤内细胞类型中通过表达干扰素-γ的T细胞增强。使用抗VEGFR 2和抗PD-L1抗体的组合的成功治疗在PyMT（多瘤中T癌蛋白）乳腺癌和RT 2-PNET（Rip 1-Tag 2胰腺神经内分泌肿瘤）中诱导了高内皮微静脉（HEV），但在胶质母细胞瘤（GBM）中未诱导。这些HEVs通过激活光敏素β受体（LTβR）信号通路促进淋巴细胞的浸润和活性。在胰腺和乳腺肿瘤中，使用激动性抗体进一步激活肿瘤血管中的LTβR信号传导增强了HEV形成、免疫以及随后的细胞凋亡和坏死。最后，LTβR激动剂在抗肿瘤GBM中诱导HEV，增强细胞毒性T细胞（CTL）活性，从而使肿瘤对抗血管生成/抗PD-L1治疗敏感。总之，我们的临床前研究提供的证据表明，抗PD-L1治疗可以使肿瘤对抗血管生成治疗敏感并延长其疗效，相反，当抗血管生成治疗产生促进增强的CTL浸润、活性和肿瘤细胞破坏的肿瘤内HEV时，可以改善抗PD-L1治疗。
Inhibitors of VEGF (vascular endothelial growth factor)/VEGFR2 (vascular endothelial growth factor receptor 2) are commonly used in the clinic, but their beneficial effects are only observed in a subset of patients and limited by induction of diverse relapse mechanisms. We describe the up-regulation of an adaptive immunosuppressive pathway during antiangiogenic therapy, by which PD-L1 (programmed cell death ligand 1), the ligand of the negative immune checkpoint regulator PD-1 (programmed cell death protein 1), is enhanced by interferon-γ–expressing T cells in distinct intratumoral cell types in refractory pancreatic, breast, and brain tumor mouse models. Successful treatment with a combination of anti-VEGFR2 and anti–PD-L1 antibodies induced high endothelial venules (HEVs) in PyMT (polyoma middle T oncoprotein) breast cancer and RT2-PNET (Rip1-Tag2 pancreatic neuroendocrine tumors), but not in glioblastoma (GBM). These HEVs promoted lymphocyte infiltration and activity through activation of lymphotoxin β receptor (LTβR) signaling. Further activation of LTβR signaling in tumor vessels using an agonistic antibody enhanced HEV formation, immunity, and subsequent apoptosis and necrosis in pancreatic and mammary tumors. Finally, LTβR agonists induced HEVs in recalcitrant GBM, enhanced cytotoxic T cell (CTL) activity, and thereby sensitized tumors to antiangiogenic/anti–PD-L1 therapy. Together, our preclinical studies provide evidence that anti–PD-L1 therapy can sensitize tumors to antiangiogenic therapy and prolong its efficacy, and conversely, antiangiogenic therapy can improve anti–PD-L1 treatment specifically when it generates intratumoral HEVs that facilitate enhanced CTL infiltration, activity, and tumor cell destruction.
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影响因子：
64.8
作者：
De Henau O;Rausch M;Winkler D;Campesato LF;Liu C;Cymerman DH;Budhu S;Ghosh A;Pink M;Tchaicha J;Douglas M;Tibbitts T;Sharma S;Proctor J;Kosmider N;White K;Stern H;Soglia J;Adams J;Palombella VJ;McGovern K;Kutok JL;Wolchok JD;Merghoub T
通讯作者：
Merghoub T
肿瘤基因对神经元和星形胶质细胞的去分化会在小鼠中诱导神经胶质瘤。
DOI：
10.1126/science.1226929
发表时间：
2012-11-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Friedmann-Morvinski D;Bushong EA;Ke E;Soda Y;Marumoto T;Singer O;Ellisman MH;Verma IM
通讯作者：
Verma IM
影响因子：
50.3
作者：
Jain RK
通讯作者：
Jain RK
影响因子：
64.5
作者：
Fischer, Christian;Jonckx, Bart;Carmeliet, Peter
通讯作者：
Carmeliet, Peter
影响因子：
50.3
作者：
Casanovas, O;Hicklin, DJ;Hanahan, D
通讯作者：
Hanahan, D