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

Naidong, Zhang, Rongping, Yin, Pei, Zhou, Xiaomei, Liu, Peng, Fan, Long, Qian, Li, Dong, Chenglin, Zhang, Xichen, Zheng, Shengming, Deng, Jiajie, Kuai, Zhenhua, Liu, Wen, Jiang, Xiaohua, Wang, Depei, Wu, Yuhui, Huang

Proceedings of the National Academy of Sciences of the United States of America |

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.