Journal Article
. 2021 May; 118(22):.
doi: 10.1073/pnas.2020057118.

DLL1 orchestrates CD8+ T cells to induce long-term vascular normalization and tumor regression

Naidong Zhang 1 Rongping Yin 2 Pei Zhou 1 Xiaomei Liu 1 Peng Fan 1 Long Qian 1 Li Dong 1 Chenglin Zhang 1 Xichen Zheng 1 Shengming Deng 1 Jiajie Kuai 1 Zhenhua Liu 1 Wen Jiang 3 Xiaohua Wang 4 Depei Wu 5 Yuhui Huang 6 
Affiliations
  • PMID: 34035167
  •     61 References
  •     2 citations

Abstract

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 γ (IFN-γ)-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-γ 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-γ-dependent manner and potentiate anti-CTLA4 therapy. Our findings unveil DLL1 as a potential target to persistently normalize the TME to facilitate cancer immunotherapy.

Keywords: Delta-like 1; cancer immunotherapy; long-term tumor vascular normalization; tumor microenvironment.

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