SOD3 induces a HIF-2α-dependent program in endothelial cells that provides a selective signal for tumor infiltration by T cells
SOD3 induces a HIF-2α-dependent program in endothelial cells that provides a selective signal for tumor infiltration by T cells
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SOD3 在内皮细胞中诱导 HIF-2α 依赖性程序，为 T 细胞的肿瘤浸润提供选择性信号
DOI：
10.1136/jitc-2019-000432
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发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Manes, Santos
中科院分区：
文献类型：
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作者：
Carmona-Rodriguez, Lorena;Martinez-Rey, Diego;Manes, Santos
肿瘤浸润淋巴细胞（til），主要是CD8（+）细胞毒性T淋巴细胞（CTL），与人类癌症的免疫介导控制和免疫治疗反应有关。尽管如此，肿瘤已经发展出选择性地限制T细胞进入肿瘤微环境的特定机制。细胞外超氧化物歧化酶（SOD3）是一种抗氧化酶，通常在肿瘤中下调。我们假设SOD3在肿瘤微环境中的上调可能是通过使肿瘤相关内皮正常化来促进T细胞浸润的一种机制。结果内皮细胞中SOD3的过表达增加了原生和活化的CD4（+）和CD8(+)T细胞的体外转运，而骨髓细胞则没有。血管周围SOD3的表达也特异性地增加了CD4（+）和CD8（+）效应T细胞向肿瘤的浸润，并提高了过继转移肿瘤特异性CD8(+)T细胞的有效性。sod3诱导的体外迁移增强和体内肿瘤浸润与T细胞趋化因子如CXCL9或CXCL10的上调无关，也与内皮粘附受体如细胞间粘附分子-1 （ICAM-1）或血管细胞粘附分子-1 （VCAM-1）水平的变化无关。相反，SOD3通过HIF-2 α依赖性诱导内皮细胞中特异性WNT配体增强T细胞浸润；这导致内皮中WNT信号通路的激活，FOXM1的稳定，以及层粘连蛋白- α 4 （LAMA4）的转录诱导，LAMA4是一种允许T细胞浸润的内皮基底膜成分。在II期结直肠癌患者中，SOD3与CD8(+)TIL密度增加和无病生存期相关。SOD3的表达也与来自癌症基因组图谱项目的COAD队列的T细胞炎症基因特征相关联。结论sod3诱导内皮细胞LAMA4表达上调，促进T淋巴细胞选择性浸润肿瘤，从而将免疫上的“冷”肿瘤转化为“热”肿瘤。高SOD3水平与人类结肠癌CD8(+)T细胞浸润有关，对这些患者的临床结果有潜在影响。我们的研究结果还揭示了一种细胞类型特异性的、WNT通路在调节T细胞浸润肿瘤中的独特活性。
Background Tumor-infiltrating lymphocytes (TILs), mainly CD8(+)cytotoxic T lymphocytes (CTL), are linked to immune-mediated control of human cancers and response to immunotherapy. Tumors have nonetheless developed specific mechanisms that selectively restrict T cell entry into the tumor microenvironment. The extracellular superoxide dismutase (SOD3) is an anti-oxidant enzyme usually downregulated in tumors. We hypothesize that upregulation of SOD3 in the tumor microenvironment might be a mechanism to boost T cell infiltration by normalizing the tumor-associated endothelium. Results Here we show that SOD3 overexpression in endothelial cells increased in vitro transmigration of naive and activated CD4(+)and CD8(+)T cells, but not of myeloid cells. Perivascular expression of SOD3 also specifically increased CD4(+)and CD8(+)effector T cell infiltration into tumors and improved the effectiveness of adoptively transferred tumor-specific CD8(+)T cells. SOD3-induced enhanced transmigration in vitro and tumor infiltration in vivo were not associated to upregulation of T cell chemokines such as CXCL9 or CXCL10, nor to changes in the levels of endothelial adhesion receptors such as intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule-1 (VCAM-1). Instead, SOD3 enhanced T cell infiltration via HIF-2 alpha-dependent induction of specific WNT ligands in endothelial cells; this led to WNT signaling pathway activation in the endothelium, FOXM1 stabilization, and transcriptional induction of laminin-alpha 4 (LAMA4), an endothelial basement membrane component permissive for T cell infiltration. In patients with stage II colorectal cancer, SOD3 was associated with increased CD8(+)TIL density and disease-free survival. SOD3 expression was also linked to a T cell-inflamed gene signature using the COAD cohort from The Cancer Genome Atlas program. Conclusion Our findings suggest that SOD3-induced upregulation of LAMA4 in endothelial cells boosts selective tumor infiltration by T lymphocytes, thus transforming immunologically "cold" into "hot" tumors. High SOD3 levels are associated with human colon cancer infiltration by CD8(+)T cells, with potential consequences for the clinical outcome of these patients. Our results also uncover a cell type-specific, distinct activity of the WNT pathway for the regulation of T cell infiltration into tumors.