Sustained Type I interferon signaling as a mechanism of resistance to PD-1 blockade Academic Article uri icon


  • 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.


  • Jacquelot, N
  • Yamazaki, T
  • Roberti, MP
  • Duong, CPM
  • Andrews, Miles C
  • Verlingue, L
  • Ferrere, G
  • Becharef, S
  • Vétizou, M
  • Daillère, R
  • Messaoudene, M
  • Enot, DP
  • Stoll, G
  • Ugel, S
  • Marigo, I
  • Foong Ngiow, S
  • Marabelle, A
  • Prevost-Blondel, A
  • Gaudreau, PO
  • Gopalakrishnan, V
  • Eggermont, AM
  • Opolon, P
  • Klein, C
  • Madonna, G
  • Ascierto, PA
  • Sucker, A
  • Schadendorf, D
  • Smyth, MJ
  • Soria, JC
  • Kroemer, G
  • Bronte, V
  • Wargo, J
  • Zitvogel, L

publication date

  • 2019