Unknown

Dataset Information

0

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


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.

SUBMITTER: Zhang N 

PROVIDER: S-EPMC8179177 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC6076221 | biostudies-literature
| S-EPMC3417121 | biostudies-literature
| S-EPMC5556362 | biostudies-other
| S-EPMC1801076 | biostudies-literature
| S-EPMC8564544 | biostudies-literature
| S-EPMC3281134 | biostudies-literature
| S-EPMC6877484 | biostudies-literature
| S-EPMC4648652 | biostudies-literature
| S-EPMC2040482 | biostudies-literature
| S-EPMC2978753 | biostudies-literature