Genome-wide gain-of-function screening characterized lncRNA regulators for tumor immune response

  • Sci Adv. 2022 Dec 9;8(49):eadd0005. doi: 10.1126/sciadv.add0005.
Yifei Wang  1 ,  Yueshan Zhao  1 ,  Weiwei Guo  1 ,  Ghanshyam Singh Yadav  2 ,  Chetana Bhaskarla  2 ,  Zehua Wang  1 ,  Xiaofei Wang  1 ,  Sihan Li  1 ,  Yue Wang  1 ,  Yuang Chen  1 ,  Dhamotharan Pattarayan  1 ,  Wen Xie  1 ,  Song Li  1 ,  Binfeng Lu  3 ,  Udai S Kammula  2  4 ,  Min Zhang  1 ,  Da Yang  1  2  5
Affiliations
  • 1. Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • 2. UPMC Hillman Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • 3. Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • 4. Division of Surgical Oncology, Department of Surgery, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
  • 5. Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
PMID: 36475797 DOI: 10.1126/sciadv.add0005
Abstract

The majority of lncRNAs' roles in tumor immunology remain elusive. This project performed a CRISPR activation screening of 9744 lncRNAs in Melanoma cells cocultured with human CD8+ T cells. We identified 16 lncRNAs potentially regulating tumor immune response. Further integrative analysis using tumor immunogenomics data revealed that IL10RB-DT and LINC01198 are significantly correlated with tumor immune response and survival in Melanoma and Breast Cancer. Specifically, IL10RB-DT suppresses CD8+ T cells activation via inhibiting IFN-γ-JAK-STAT1 signaling and antigen presentation in Melanoma and Breast Cancer cells. On the other hand, LINC01198's up-regulation sensitizes the killing of tumor cells by CD8+ T cells. Mechanistically, LINC01198 interacts and activates NF-κB component p65 to trigger the type I and type II interferon responses in Melanoma and Breast Cancer cells. Our study systematically characterized novel lncRNAs involved in tumor immune response.

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