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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-06, Vol.118 (22), p.1-9
• Main Authors: Zhang, Naidong, Yin, Rongping, Zhou, Pei, Liu, Xiaomei, Fan, Peng, Qian, Long, Dong, Li, Zhang, Chenglin, Zheng, Xichen, Deng, Shengming, Kuai, Jiajie, Liu, Zhenhua, Jiang, Wen, Wang, Xiaohua, Wu, Depei, Huang, Yuhui
• Format: Article
• Language: English
• Subjects: Biological Sciences; Breast; Cancer; Cancer immunotherapy; CD8 antigen; CTLA-4 protein; Cytotoxicity; DELTA protein; Depletion; Growth inhibition; Hypoxia; Immunotherapy; Interferon; Lymphocytes; Lymphocytes T; Macrophages; Polarization; Tumor microenvironment; Tumors; γ-Interferon
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2020057118

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.