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Sustained Type I interferon signaling as a mechanism of resistance to PD-1 blockade.
- Source :
-
Cell research [Cell Res] 2019 Oct; Vol. 29 (10), pp. 846-861. Date of Electronic Publication: 2019 Sep 03. - Publication Year :
- 2019
-
Abstract
- PD-1 blockade represents a major therapeutic avenue in anticancer immunotherapy. Delineating mechanisms of secondary resistance to this strategy is increasingly important. Here, we identified the deleterious role of signaling via the type I interferon (IFN) receptor in tumor and antigen presenting cells, that induced the expression of nitric oxide synthase 2 (NOS2), associated with intratumor accumulation of regulatory T cells (Treg) and myeloid cells and acquired resistance to anti-PD-1 monoclonal antibody (mAb). Sustained IFNβ transcription was observed in resistant tumors, in turn inducing PD-L1 and NOS2 expression in both tumor and dendritic cells (DC). Whereas PD-L1 was not involved in secondary resistance to anti-PD-1 mAb, pharmacological or genetic inhibition of NOS2 maintained long-term control of tumors by PD-1 blockade, through reduction of Treg and DC activation. Resistance to immunotherapies, including anti-PD-1 mAb in melanoma patients, was also correlated with the induction of a type I IFN signature. Hence, the role of type I IFN in response to PD-1 blockade should be revisited as sustained type I IFN signaling may contribute to resistance to therapy.
- Subjects :
- Animals
Antibodies, Monoclonal immunology
Antibodies, Monoclonal therapeutic use
B7-H1 Antigen metabolism
Cell Line, Tumor
Dendritic Cells cytology
Dendritic Cells metabolism
Drug Resistance, Neoplasm
Humans
Kaplan-Meier Estimate
Melanoma drug therapy
Melanoma mortality
Melanoma pathology
Mice
Mice, Inbred C57BL
Neoplasms drug therapy
Neoplasms mortality
Neoplasms pathology
Nitric Oxide Synthase Type II metabolism
T-Lymphocytes, Regulatory cytology
T-Lymphocytes, Regulatory immunology
T-Lymphocytes, Regulatory metabolism
Antibodies, Monoclonal pharmacology
Interferon Type I metabolism
Programmed Cell Death 1 Receptor immunology
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1748-7838
- Volume :
- 29
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cell research
- Publication Type :
- Academic Journal
- Accession number :
- 31481761
- Full Text :
- https://doi.org/10.1038/s41422-019-0224-x