Sustained Type I interferon signaling as a mechanism of resistance to PD-1 blockade

Nicolas Jacquelot, Takahiro Yamazaki, Maria P. Roberti, Connie P.M. Duong, Miles C. Andrews, Loic Verlingue, Gladys Ferrere, Sonia Becharef, Marie Vétizou, Romain Daillère, Meriem Messaoudene, David P. Enot, Gautier Stoll, Stefano Ugel, Ilaria Marigo, Shin Foong Ngiow, Aurélien Marabelle, Armelle Prevost-Blondel, Pierre Olivier Gaudreau, Vancheswaran GopalakrishnanAlexander M. Eggermont, Paule Opolon, Christophe Klein, Gabriele Madonna, Paolo A. Ascierto, Antje Sucker, Dirk Schadendorf, Mark J. Smyth, Jean Charles Soria, Guido Kroemer, Vincenzo Bronte, Jennifer Wargo, Laurence Zitvogel

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
JournalCell Research
Publication statusPublished - 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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