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

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.

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.

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.

Metrics

  • 825
    views
  • 11
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Cancer Biology
    Han V Han, Richard Efem ... Richard Z Lin
    Research Article

    Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca−/− KPC (named αKO) cancer cells induces clonal enrichment of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in αKO cells (named p-αKO) leads to immune evasion, tumor progression, and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally enriched CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally enriched T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.

    1. Cancer Biology
    2. Immunology and Inflammation
    Almudena Mendez-Perez, Andres M Acosta-Moreno ... Esteban Veiga
    Short Report

    In this study, we present a proof-of-concept classical vaccination experiment that validates the in silico identification of tumor neoantigens (TNAs) using a machine learning-based platform called NAP-CNB. Unlike other TNA predictors, NAP-CNB leverages RNA-seq data to consider the relative expression of neoantigens in tumors. Our experiments show the efficacy of NAP-CNB. Predicted TNAs elicited potent antitumor responses in mice following classical vaccination protocols. Notably, optimal antitumor activity was observed when targeting the antigen with higher expression in the tumor, which was not the most immunogenic. Additionally, the vaccination combining different neoantigens resulted in vastly improved responses compared to each one individually, showing the worth of multiantigen-based approaches. These findings validate NAP-CNB as an innovative TNA identification platform and make a substantial contribution to advancing the next generation of personalized immunotherapies.