Neutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer
Immune checkpoint inhibitors can improve the prognosis of patients with advanced malignancy; however, only a small subset of advanced colorectal cancer patients in microsatellite-instability-high or mismatch-repair-deficient colorectal cancer can benefit from immunotherapy. Unfortunately, the mechan...
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| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | article |
| Language: | EN |
| Published: |
MDPI AG
2021
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| Subjects: | |
| Online Access: | https://doaj.org/article/d03d5215526a4b78bf8b3f90f9e5f9bf |
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| Summary: | Immune checkpoint inhibitors can improve the prognosis of patients with advanced malignancy; however, only a small subset of advanced colorectal cancer patients in microsatellite-instability-high or mismatch-repair-deficient colorectal cancer can benefit from immunotherapy. Unfortunately, the mechanism behind this ineffectiveness is unclear. The tumor microenvironment plays a critical role in cancer immunity, and may contribute to the inhibition of immune checkpoint inhibitors and other novel immunotherapies in patients with advanced cancer. Herein, we demonstrate that the DNase I enzyme plays a pivotal role in the degradation of NETs, significantly dampening the resistance to anti-PD-1 blockade in a mouse colorectal cancer model by attenuating tumor growth. Remarkably, DNase I decreases tumor-associated neutrophils and the formation of MC38 tumor cell-induced neutrophil extracellular trap formation in vivo. Mechanistically, the inhibition of neutrophil extracellular traps with DNase I results in the reversal of anti-PD-1 blockade resistance through increasing CD8+ T cell infiltration and cytotoxicity. These findings signify a novel approach to targeting the tumor microenvironment using DNase I alone or in combination with immune checkpoint inhibitors. |
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