期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2020057118
关键词
Delta-like 1; long-term tumor vascular normalization; tumor microenvironment; cancer immunotherapy
资金
- National Program on Key Research Project of China [2016YFC1302400]
- National Natural Science Foundation of China [81972877, 81372245]
- State Key Laboratory of Radiation Medicine and Prevention [GZN1201904]
- Collaborative Innovation Center of Hematology
- Priority Academic Program Development of Jiangsu Higher Education Institutions
Elevated levels of DLL1 in the TME promote long-term tumor vascular normalization, accumulation of CD8+ T cells, M1-like macrophage polarization, and increase the sensitivity of anti-CTLA4 therapy in resistant tumors.
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.
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