VPS9D1-AS1 overexpression amplifies intratumoral TGF-β signaling and promotes tumor cell escape from CD8+ T cell killing in colorectal cancer
- Beijing Chao-Yang Hospital, China
- 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).
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VPS9D1-AS1 regualtes differential mRNA in HCT116 cellsSequence Read Archive, PRJNA716724.
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Overexpression of VPS9D1-AS1, an activator of transforming growth factor β signaling, upregulates interferon-stimulated-gene expression to regress CD8+ T cell infiltration in the microenvironment of colorectal cancer.Dryad Digital Repository, doi:10.5061/dryad.qnk98sfk6.
Article and author information
Author details
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.
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