1. Cancer Biology
  2. Immunology and Inflammation

VPS9D1-AS1 overexpression amplifies intratumoral TGF-β signaling and promotes tumor cell escape from CD8+ T cell killing in colorectal cancer

  1. Lei Yang  Is a corresponding author
  2. Xichen Dong
  3. Zheng Liu
  4. Jinjing Tan
  5. Xiaoxi Huang
  6. Tao Wen
  7. Hao Qu  Is a corresponding author
  8. Zhenjun Wang  Is a corresponding author
  1. Beijing Chao-Yang Hospital, China
  2. Beijing Chest Hospital, China
https://doi.org/10.7554/eLife.79811
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Cite this article
  1. Lei Yang
  2. Xichen Dong
  3. Zheng Liu
  4. Jinjing Tan
  5. Xiaoxi Huang
  6. Tao Wen
  7. Hao Qu
  8. Zhenjun Wang
(2022)
VPS9D1-AS1 overexpression amplifies intratumoral TGF-β signaling and promotes tumor cell escape from CD8+ T cell killing in colorectal cancer
eLife 11:e79811.
https://doi.org/10.7554/eLife.79811
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Abstract

Efficacy of immunotherapy is limited in patients with colorectal cancer (CRC) because high expression of tumor-derived transforming growth factor (TGF)-β pathway molecules and interferon (IFN)-stimulated genes (ISGs) promotes tumor immune evasion. Here, we identified a long noncoding RNA (lncRNA), VPS9D1-AS1, which was located in ribosomes and amplified TGF-β signaling and ISG expression. We show that high expression of VPS9D1-AS1 was negatively associated with T lymphocyte infiltration in two independent cohorts of CRC. VPS9D1-AS1 served as a scaffolding lncRNA by binding with ribosome protein S3 (RPS3) to increase the translation of TGF-β, TGFBR1, and SMAD1/5/9. VPS9D1-AS1 knockout downregulated OAS1, an ISG gene, which further reduced IFNAR1 levels in tumor cells. Conversely, tumor cells overexpressing VPS9D1-AS1 were resistant to CD8+ T cell killing and lowered IFNAR1 expression in CD8+ T cells. In a conditional overexpression mouse model, VPS9D1-AS1 enhanced tumorigenesis and suppressed the infiltration of CD8+ T cells. Treating tumor-bearing mice with antisense oligonucleotide drugs targeting VPS9D1-AS1 significantly suppressed tumor growth. Our findings indicate that the tumor-derived VPS9D1-AS1/TGF-β/ISG signaling cascade promotes tumor growth and enhances immune evasion and may thus serve as a potential therapeutic target for CRC.

Data availability

RNA sequencing data set of HCT116 sgControl and sgVPS cells were deposited in Sequence Read Archive (PRJNA716724) and Dryad Digital Repository (10.5061/dryad.qnk98sfk6).

The following data sets were generated

Article and author information

Author details

  1. Lei Yang

    Medical Research Center, Beijing Chao-Yang Hospital, Beijing, China
    For correspondence
    yl6649084@mail.ccmu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3718-2138

  2. Xichen Dong

    Medical Research Center, Beijing Chao-Yang Hospital, Beijign, China
    Competing interests
    The authors declare that no competing interests exist.

  3. Zheng Liu

    Medical Research Center, Beijing Chao-Yang Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.

  4. Jinjing Tan

    Department of Cellular and Molecular Biology, Beijing Chest Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.

  5. Xiaoxi Huang

    Medical Research Center, Beijing Chao-Yang Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.

  6. Tao Wen

    Medical Research Center, Beijing Chao-Yang Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.

  7. Hao Qu

    Department of General Surgery, Beijing Chao-Yang Hospital, Beijing, China
    For correspondence
    13701320206@163.com
    Competing interests
    The authors declare that no competing interests exist.

  8. Zhenjun Wang

    Department of General Surgery, Beijing Chao-Yang Hospital, Beijing, China
    For correspondence
    drzhenjun@163.com
    Competing interests
    The authors declare that no competing interests exist.

Funding

Natural Science Foundation of China (81802349)

  • Lei Yang

National Science Foundation of China (8213234)

  • Tao Wen

Beijing Natural Science Foundation (7192070)

  • Lei Yang

Beijing Municipal of Hospitals Incubating Program (PX2018013)

  • Lei Yang

Scientific Research Project of Beijing Educational Committee (KM20190025016)

  • Lei Yang

Open Project of Key Laboratory of Cardiovascular Disease Medical Engineering, Ministry of Education (2019XXG-KFKT-03)

  • Lei Yang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Caigang Liu, Shengjing Hospital of China Medical University, China

Ethics

Animal experimentation: Animal experimental protocols were approved (AEEI-2021-105) according to the guidelines of the Ethics Committee for Animal Testing of Capital Medical University.

Human subjects: All sample donors provided informed consent, and the study was conducted under the approval (2018-ke-24) of the Institutional Ethics Committee from Beijing Chaoyang Hospital of Capital Medical University between 2018 and 2020 samples were collected from patients with CRC who did not receive chemotherapy or radiotherapy before surgery.

Version history

  1. Received: April 27, 2022
  2. Preprint posted: May 13, 2022 (view preprint)
  3. Accepted: December 1, 2022
  4. Accepted Manuscript published: December 2, 2022 (version 1)
  5. Version of Record published: December 12, 2022 (version 2)

Copyright

© 2022, Yang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Lei Yang
  2. Xichen Dong
  3. Zheng Liu
  4. Jinjing Tan
  5. Xiaoxi Huang
  6. Tao Wen
  7. Hao Qu
  8. Zhenjun Wang
(2022)
VPS9D1-AS1 overexpression amplifies intratumoral TGF-β signaling and promotes tumor cell escape from CD8+ T cell killing in colorectal cancer
eLife 11:e79811.
https://doi.org/10.7554/eLife.79811

Share this article

https://doi.org/10.7554/eLife.79811

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