LIMIT is an immunogenic lncRNA in cancer immunity and immunotherapy

Abstract

MHC-I presents tumor antigens to CD8 ⁺ T cells and triggers anti-tumor immunity. Humans may have 30,000-60,000 long noncoding RNAs (lncRNAs). However, it remains poorly understood whether lncRNAs may affect tumor immunity. Here, we identify a LncRNA, capable of Inducing MHC-I and Immunogenicity of Tumor (LIMIT) in humans and mice. We found IFNγ stimulated LIMIT, LIMIT cis-activated 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 tumor immunogenicity and checkpoint therapy. Silencing LIMIT, GBPs, and/or HSF1 diminished MHC-I, impaired antitumor immunity, and blunted immunotherapy efficacy. Clinically, LIMIT, GBPs- and HSF1-signaling transcripts and proteins correlated with MHC-I, tumor infiltrating T cells, and checkpoint blockade response in cancer patients. Altogether, we demonstrate LIMIT is a previously unknown cancer immunogenic lncRNA and the LIMIT-GBP-HSF1 axis may be targetable for cancer immunotherapy.