LIMIT is an immunogenic lncRNA in cancer immunity and immunotherapy

• Published in: Nature cell biology Vol. 23; no. 5; pp. 526 - 537
• Main Authors: Li, Gaopeng, Kryczek, Ilona, Nam, Jutaek, Li, Xiong, Li, Shasha, Li, Jing, Wei, Shuang, Grove, Sara, Vatan, Linda, Zhou, Jiajia, Du, Wan, Lin, Heng, Wang, Ton, Subramanian, Chitra, Moon, James J, Cieslik, Marcin, Cohen, Mark, Zou, Weiping
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.05.2021
• Subjects: Antigens; Antigens, Neoplasm - immunology; Cancer; Cancer immunotherapy; Care and treatment; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; CRISPR; Gene expression; Genetic aspects; Guanylate-binding protein; Health aspects; Heat shock; Heat shock factors; Heat shock proteins; HSF1 protein; HSP90 Heat-Shock Proteins - metabolism; Hsp90 protein; Humans; Identification and classification; Immune checkpoint; Immune response; Immune system; Immunity; Immunogenicity; Immunotherapy; Immunotherapy - methods; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - metabolism; Oncology, Experimental; PD-L1 protein; Proteins; RNA; RNA, Long Noncoding - genetics; Signal Transduction - physiology; Transcription activation; Tumors; γ-Interferon; United States
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-021-00672-3

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.