Dual role of endothelial Myct1 in tumor angiogenesis and tumor immunity.
Dual role of endothelial Myct1 in tumor angiogenesis and tumor immunity.
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DOI：
10.1126/scitranslmed.abb6731
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发表时间：
2021-03-03
影响因子：
17.1
通讯作者：
Choi K
中科院分区：
文献类型：
--
作者：
Kabir AU;Subramanian M;Lee DH;Wang X;Krchma K;Wu J;Naismith T;Halabi CM;Kim JY;Pulous FE;Petrich BG;Kim S;Park HC;Hanson PI;Pan H;Wickline SA;Fremont DH;Park C;Choi K
肿瘤微环境(TME)中血管生成和免疫之间的相互作用对肿瘤预后至关重要。促血管生成和免疫抑制的TME促进肿瘤生长，抗血管生成和免疫刺激的TME抑制肿瘤的进展。因此，实现血管正常化对改善药物输送和增强抗肿瘤免疫能力具有重要意义。然而，抗血管内皮生长因子(VEGF)使肿瘤血管正常化的机制对癌症患者的治疗效果有限。在此，我们报道了ETV2的直接靶标Myct1几乎只在内皮细胞中表达。在临床前小鼠肿瘤模型中，Myct1缺乏减少血管生成，促进高内皮微静脉形成，促进抗肿瘤免疫环境，导致Myct1基因敲除小鼠肿瘤进展受限。对癌症基因组图谱(TCGA)数据集的分析显示，在人类癌症中，MYCT1的表达、血管生成和抗肿瘤免疫之间存在显著的相关性(p<；0.05)，这表明在MYCT1低表达的患者中，FOXP3表达降低，抗肿瘤巨噬细胞增加。在机制上，MYCT1与紧密连接蛋白Zona Occludens 1相互作用，调节Rho GTPase介导的肌动蛋白细胞骨架动力学，从而促进血管生成环境中的内皮运动。Myct1缺陷的内皮细胞促进了细胞毒性T淋巴细胞的跨内皮迁移和M1巨噬细胞的极化。Myct1靶向联合抗PD1治疗显著(p<；0.05)增加了抗PD1反应和难治性肿瘤模型小鼠的肿瘤完全消退和长期存活率。我们的数据共同支持Myct1在控制肿瘤血管生成和重新编程肿瘤免疫方面的关键作用。以Myct1为靶点的血管控制与免疫治疗相结合，可能成为一种令人兴奋的治疗策略。Myct1抑制控制肿瘤血管生成，重塑肿瘤免疫，并改善小鼠肿瘤模型的免疫治疗结果。
The crosstalk between angiogenesis and immunity within the tumor microenvironment (TME) is critical for tumor prognosis. While pro-angiogenic and immunosuppressive TME promote tumor growth, anti-angiogenic and immune stimulatory TME inhibit tumor progression. Therefore, there is a great interest in achieving vascular normalization to improve drug delivery and enhance anti-tumor immunity. However, anti-vascular endothelial growth factor (VEGF) mechanisms to normalize tumor vessels have offered limited therapeutic efficacies for cancer patients. Herein, we report that Myct1, a direct target of ETV2, was nearly exclusively expressed in endothelial cells. In preclinical mouse tumor models, Myct1 deficiency reduced angiogenesis, enhanced high endothelial venule formation, and promoted an anti-tumor immune environment, leading to restricted tumor progression in Myct1 knockout mice. Analysis of The Cancer Genome Atlas (TCGA) datasets revealed a significant (p<0.05) correlation between MYCT1 expression, angiogenesis, and anti-tumor immunity in human cancers, as suggested by the decreased FOXP3 expression and increased anti-tumor macrophages in patients with low MYCT1 expression. Mechanistically, MYCT1 interacted with tight junction protein Zona Occludens 1 and regulated Rho GTPase-mediated actin cytoskeleton dynamics, thereby promoting endothelial motility in the angiogenic environment. Myct1-deficient endothelial cells facilitated trans-endothelial migration of cytotoxic T lymphocytes and polarization of M1 macrophages. Myct1 targeting combined with anti-PD1 treatment significantly (p<0.05) increased complete tumor regression and long-term survival in anti-PD1-responsive and -refractory tumor models in mice. Our data collectively support a critical role for Myct1 in controlling tumor angiogenesis and reprogramming tumor immunity. Myct1-targeted vascular control, in combination with immunotherapy, may become an exciting therapeutic strategy. Myct1 inhibition controls tumor angiogenesis, remodels tumor immunity, and improves immunotherapy outcomes in mouse tumor models.
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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：
4.6
作者：
D'Costa, Ninadh M.;Cina, Davide;So, Alan I.
通讯作者：
So, Alan I.
DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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影响因子：
120.1
作者：
Ferrara, Napoleone;Adamis, Anthony P.
通讯作者：
Adamis, Anthony P.
影响因子：
5.3
作者：
GUY, CT;CARDIFF, RD;MULLER, WJ
通讯作者：
MULLER, WJ