Tumor Interferon Signaling Is Regulated by a lncRNA INCR1 Transcribed from the PD-L1 Locus

Mol Cell. 2020 Jun 18;78(6):1207-1223.e8. doi: 10.1016/j.molcel.2020.05.015. Epub 2020 Jun 5.


Tumor interferon (IFN) signaling promotes PD-L1 expression to suppress T cell-mediated immunosurveillance. We identify the IFN-stimulated non-coding RNA 1 (INCR1) as a long noncoding RNA (lncRNA) transcribed from the PD-L1 locus and show that INCR1 controls IFNγ signaling in multiple tumor types. Silencing INCR1 decreases the expression of PD-L1, JAK2, and several other IFNγ-stimulated genes. INCR1 knockdown sensitizes tumor cells to cytotoxic T cell-mediated killing, improving CAR T cell therapy. We discover that PD-L1 and JAK2 transcripts are negatively regulated by binding to HNRNPH1, a nuclear ribonucleoprotein. The primary transcript of INCR1 binds HNRNPH1 to block its inhibitory effects on the neighboring genes PD-L1 and JAK2, enabling their expression. These findings introduce a mechanism of tumor IFNγ signaling regulation mediated by the lncRNA INCR1 and suggest a therapeutic target for cancer immunotherapy.

Keywords: CAR T cell therapy; HNRNPH1; INCR1; JAK2; PD-L1; cancer; interferon signaling; long noncoding RNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • B7-H1 Antigen / genetics*
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Immunotherapy
  • Immunotherapy, Adoptive / methods
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism*
  • Interferons / genetics
  • Interferons / metabolism
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism
  • Male
  • Mice
  • Mice, Inbred NOD
  • Middle Aged
  • Programmed Cell Death 1 Ligand 2 Protein / genetics
  • RNA, Long Noncoding / genetics*
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • T-Lymphocytes, Cytotoxic


  • B7-H1 Antigen
  • CD274 protein, human
  • PDCD1LG2 protein, human
  • Programmed Cell Death 1 Ligand 2 Protein
  • RNA, Long Noncoding
  • STAT1 Transcription Factor
  • Interferon-gamma
  • Interferons
  • JAK2 protein, human
  • Janus Kinase 2