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
Pages (from-to)846-861
Number of pages16
JournalCell Research
Issue number10
Publication statusPublished - Oct 2019


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