1. LIMIT is an immunogenic lncRNA in cancer immunity and immunotherapy
- Author
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Jutaek Nam, Ilona Kryczek, Heng Lin, Chitra Subramanian, James J. Moon, Jing Li, Shuang Wei, Wan Du, Sara Grove, Gaopeng Li, Ton Wang, Mark S. Cohen, Jiajia Zhou, Weiping Zou, Linda Vatan, Marcin Cieslik, Shasha Li, and Xiong Li
- Subjects
PD-L1 ,medicine.medical_treatment ,GBP ,chemical and pharmacologic phenomena ,CD8-Positive T-Lymphocytes ,Biology ,HSF1 ,Major histocompatibility complex ,LIMIT ,Article ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cancer immunotherapy ,Antigens, Neoplasm ,Cell Line, Tumor ,Neoplasms ,PD-1 ,MHC-I ,medicine ,HSP90 ,Humans ,Gene silencing ,HSP90 Heat-Shock Proteins ,Cell Proliferation ,030304 developmental biology ,0303 health sciences ,cancer immunotherapy ,T cell immunity ,Immunogenicity ,fungi ,Cell Biology ,Immunotherapy ,Cell biology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,RNA, Long Noncoding ,CD8 ,Signal Transduction ,Long noncoding RNA ,IFNγ - Abstract
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. Li et al. identify LIMIT as a lncRNA that modulates MHC-I expression through HSP90 and HSF1, thereby regulating antitumour immune response and the efficacy of immunotherapy.
- Published
- 2021