VEGFR2 activity on myeloid cells mediates immune suppression in the tumor microenvironment.
VEGFR2 activity on myeloid cells mediates immune suppression in the tumor microenvironment.
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DOI：
10.1172/jci.insight.150735
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发表时间：
2021-12-08
期刊：
影响因子：
8
通讯作者：
Brekken RA
中科院分区：
文献类型：
--
作者：
Zhang Y;Huang H;Coleman M;Ziemys A;Gopal P;Kazmi SM;Brekken RA
血管生成是肿瘤的一个标志，是由血管内皮生长因子-A(以下简称血管内皮生长因子)诱导的。因此，抗血管内皮生长因子治疗被广泛应用于癌症的治疗。最近的研究发现，在癌症患者中，血管内皮生长因子的表达也与免疫抑制有关。这种联系已经在临床前和临床研究中通过评估抗血管生成试剂与免疫治疗的治疗效果进行了研究。然而，抗血管内皮生长因子策略如何增强免疫治疗的机制还不完全清楚。我们和其他人已经发现，在荷瘤动物中，肿瘤相关髓细胞上VEGFR2的表达有选择性地升高。在这里，我们研究了VEGFR2+髓系细胞在调节肿瘤免疫中的作用，发现VEGF诱导VEGFR2+髓系细胞的免疫抑制表型，包括直接上调程序性细胞死亡1配体1的表达。此外，我们还发现，VEGF阻断抑制了VEGFR2+髓系细胞的免疫抑制表型，增加了T细胞的激活，并增强了免疫检查点阻断的效果。这项研究强调了VEGFR2在髓系细胞上的功能，并提供了关于血管内皮生长因子抑制如何加强免疫检查点阻断的机制见解。
Angiogenesis, a hallmark of cancer, is induced by vascular endothelial growth factor–A (hereafter VEGF). As a result, anti-VEGF therapy is commonly used for cancer treatment. Recent studies have found that VEGF expression is also associated with immune suppression in patients with cancer. This connection has been investigated in preclinical and clinical studies by evaluating the therapeutic effect of combining antiangiogenic reagents with immune therapy. However, the mechanisms of how anti-VEGF strategies enhance immune therapy are not fully understood. We and others have shown selective elevation of VEGFR2 expression on tumor-associated myeloid cells in tumor-bearing animals. Here, we investigated the function of VEGFR2+ myeloid cells in regulating tumor immunity and found VEGF induced an immunosuppressive phenotype in VEGFR2+ myeloid cells, including directly upregulating the expression of programmed cell death 1 ligand 1. Moreover, we found that VEGF blockade inhibited the immunosuppressive phenotype of VEGFR2+ myeloid cells, increased T cell activation, and enhanced the efficacy of immune checkpoint blockade. This study highlights the function of VEGFR2 on myeloid cells and provides mechanistic insight on how VEGF inhibition potentiates immune checkpoint blockade.
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影响因子：
30.5
作者：
Agudo, Judith;Ruzo, Albert;Tung, Navpreet;Salmon, Helene;Leboeuf, Marylene;Hashimoto, Daigo;Becker, Christian;Garrett-Sinha, Lee-Ann;Baccarini, Alessia;Merad, Miriam;Brown, Brian D.
通讯作者：
Brown, Brian D.
影响因子：
10.1
作者：
Hodi FS;Lawrence D;Lezcano C;Wu X;Zhou J;Sasada T;Zeng W;Giobbie-Hurder A;Atkins MB;Ibrahim N;Friedlander P;Flaherty KT;Murphy GF;Rodig S;Velazquez EF;Mihm MC Jr;Russell S;DiPiro PJ;Yap JT;Ramaiya N;Van den Abbeele AD;Gargano M;McDermott D
通讯作者：
McDermott D
影响因子：
17.1
作者：
Allen E;Jabouille A;Rivera LB;Lodewijckx I;Missiaen R;Steri V;Feyen K;Tawney J;Hanahan D;Michael IP;Bergers G
通讯作者：
Bergers G
影响因子：
12.4
作者：
Lasaro, Marcio O.;Sazanovich, Marina;Ertl, Hildegund C. J.
通讯作者：
Ertl, Hildegund C. J.
DOI：
10.1073/pnas.1902145116
发表时间：
2020-01-07
影响因子：
11.1
作者：
Kashyap, Abhishek S.;Schmittnaegel, Martina;Zippelius, Alfred
通讯作者：
Zippelius, Alfred