LIMIT is an immunogenic lncRNA in cancer immunity and immunotherapy

Nat Cell Biol. 2021 May;23(5):526-537. doi: 10.1038/s41556-021-00672-3. Epub 2021 May 6.


Major histocompatibility complex-I (MHC-I) presents tumour antigens to CD8+ T cells and triggers anti-tumour immunity. Humans may have 30,000-60,000 long noncoding RNAs (lncRNAs). However, it remains poorly understood whether lncRNAs affect tumour immunity. Here, we identify a lncRNA, lncRNA inducing MHC-I and immunogenicity of tumour (LIMIT), in humans and mice. We found that IFNγ stimulated LIMIT, LIMIT cis-activated the guanylate-binding protein (GBP) gene cluster and GBPs disrupted the association between HSP90 and heat shock factor-1 (HSF1), thereby resulting in HSF1 activation and transcription of MHC-I machinery, but not PD-L1. RNA-guided CRISPR activation of LIMIT boosted GBPs and MHC-I, and potentiated tumour immunogenicity and checkpoint therapy. Silencing LIMIT, GBPs and/or HSF1 diminished MHC-I, impaired antitumour immunity and blunted immunotherapy efficacy. Clinically, LIMIT, GBP- and HSF1-signalling transcripts and proteins correlated with MHC-I, tumour-infiltrating T cells and checkpoint blockade response in patients with cancer. Together, we demonstrate that LIMIT is a cancer immunogenic lncRNA and the LIMIT-GBP-HSF1 axis may be targetable for cancer immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigens, Neoplasm / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Immunotherapy* / methods
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Neoplasms / metabolism*
  • RNA, Long Noncoding / genetics*
  • Signal Transduction / physiology


  • Antigens, Neoplasm
  • HSP90 Heat-Shock Proteins
  • RNA, Long Noncoding