DLL1 orchestrates CD8+T cells to induce long-term vascular normalization and tumor regression
DLL1 orchestrates CD8+T cells to induce long-term vascular normalization and tumor regression
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DOI：
10.1073/pnas.2020057118
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发表时间：
2021-06-01
影响因子：
11.1
通讯作者：
Huang, Yuhui
中科院分区：
文献类型：
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作者：
Zhang, Naidong;Yin, Rongping;Huang, Yuhui
免疫抑制和缺氧的肿瘤微环境（TME）仍然是阻碍癌症免疫治疗的主要障碍。在这里，我们发现，乳腺和肺TME中Delta样1（DLL 1）水平升高诱导长期肿瘤血管正常化，以减轻肿瘤缺氧，并促进表达干扰素γ（IFN-γ）的CD 8 + T细胞的积累和M1样巨噬细胞的极化。此外，TME中增加的DLL 1水平使其耐药肿瘤中的抗细胞毒性T淋巴细胞相关蛋白4（抗CTLA 4）治疗敏化，导致肿瘤消退和延长存活。在机械上，体内消耗CD 8 + T细胞或宿主IFN-γ缺乏逆转了肿瘤生长抑制并废除了DLL 1诱导的肿瘤血管正常化，而不影响DLL 1介导的巨噬细胞极化。总之，这些结果表明，TME中DLL 1水平升高以CD 8 + T细胞和IFN-γ依赖性方式促进持久的肿瘤血管正常化，并增强抗CTLA 4治疗。我们的研究结果揭示了DLL 1作为持续正常化TME以促进癌症免疫治疗的潜在靶点。
The immunosuppressive and hypoxic tumor microenvironment (TME) remains a major obstacle to impede cancer immunotherapy. Here, we showed that elevated levels of Delta-like 1 (DLL1) in the breast and lung TME induced long-term tumor vascular normalization to alleviate tumor hypoxia and promoted the accumulation of interferon gamma (IFN-gamma)-expressing CD8+ T cells and the polarization of M1-like macrophages. Moreover, increased DLL1 levels in the TME sensitized anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA4) treatment in its resistant tumors, resulting in tumor regression and prolonged survival. Mechanically, in vivo depletion of CD8+ T cells or host IFN-gamma deficiency reversed tumor growth inhibition and abrogated DLL1-induced tumor vascular normalization without affecting DLL1-mediated macrophage polarization. Together, these results demonstrate that elevated DLL1 levels in the TME promote durable tumor vascular normalization in a CD8+ T cell- and IFN-gamma-dependent manner and potentiate anti-CTLA4 therapy. Our findings unveil DLL1 as a potential target to persistently normalize the TME to facilitate cancer immunotherapy.