期刊
CELL RESEARCH
卷 29, 期 10, 页码 846-861出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41422-019-0224-x
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资金
- Institut National du Cancer (INCa)
- ANR
- Ligue contre le cancer
- Swiss Bridge Foundation
- ISREC Foundation
- Universite Paris-Sud, PIA2 TORINO-LUMIERE
- Fondation pour la Recherche Medicale (FRM)
- European Research Area Network on Cardiovascular Diseases
- Gustave Roussy Odyssea
- European Union
- Fondation Carrefour
- Inserm (HTE)
- Institut Universitaire de France
- LeDucq Foundation
- LabEx Immuno-Oncology
- RHU Torino Lumiere
- Seerave Foundation
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- Fondation ARC pour la recherche sur le cancer [1163990]
- Cancer Australia and Cure Cancer
- National Health and Medical Research Council (NHMRC) of Australia CJ Martin Early Career Fellowship [1148680]
- Lyda Hill Foundation
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- AIM at Melanoma Foundation
- Italian Miinistry of Health through Ricerca Corrente - Istitutional Ricerca Corrente
- NHMRC of Australia Senior Principal Research Fellowship [1078671, 1132519]
- Italian Association for Cancer Research [AIRC 12182, 21509, 18603]
- Australia NHMRC CJ Martin Fellowship [1111469]
- National Health and Medical Research Council of Australia [1111469] Funding Source: NHMRC
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 IFN beta 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.
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