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Cited by 22Ocular Oncology and TreatmentsCancer Immunotherapy and BiomarkersImmunotherapy and Immune Responses

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Long-Read Sequencing Reveals Alternative Splicing-Driven, Shared Immunogenic Neoepitopes Regardless of SF3B1 Status in Uveal Melanoma

Yao, Tengteng, Zhang, Zhe, Li, Qian, Huang, Rui, Hong, Yanhong, Li, Chen, Zhang, Feng, Huang, Yingying, Fang, Yan, Cao, Qin, Jin, Xiaoliang, Li, Chunliang, Wang, Zefeng, Lin, Xinhua (James), Li, Lingjie, Wei, Wu, Wang, Zhaoyang, Shen, Jianfeng·2023·Cancer Immunology Research
DOI 10.1158/2326-6066.cir-23-0083

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Abstract

Tumor-specific neoepitopes are promising targets in cancer immunotherapy. However, the identification of functional tumor-specific neoepitopes remains challenging. In addition to the most common source, single-nucleotide variants (SNV), alternative splicing (AS) represents another rich source of neoepitopes and can be utilized in cancers with low SNVs such as uveal melanoma (UM). UM, the most prevalent adult ocular malignancy, has poor clinical outcomes due to a lack of effective therapies. Recent studies have revealed the promise of harnessing tumor neoepitopes to treat UM. Previous studies have focused on neoepitope targets associated with mutations in splicing factor 3b subunit 1 (SF3B1), a key splicing factor; however, little is known about the neoepitopes that are commonly shared by patients independent of SF3B1 status. To identify the AS-derived neoepitopes regardless of SF3B1 status, we herein used a comprehensive nanopore long-read-sequencing approach to elucidate the landscape of AS and novel isoforms in UM. We also performed high-resolution mass spectrometry to further validate the presence of neoepitope candidates and analyzed their structures using the AlphaFold2 algorithm. We experimentally evaluated the antitumor effects of these neoepitopes and found they induced robust immune responses by stimulating interferon (IFN)γ production and activating T cell–based UM tumor killing. These results provide novel insights into UM-specific neoepitopes independent of SF3B1 and lay the foundation for developing therapies by targeting these actionable neoepitopes.

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Metadata

Authors
Yao, T., Zhang, Z., Li, Q., Huang, R., Hong, Y., Li, C., Zhang, F., Huang, Y., Fang, Y., Cao, Q., Jin, X., Li, C., Wang, Z., Lin, X. (., Li, L., Wei, W., Wang, Z., & Shen, J.
Affiliations
  • Shanghai Jiao Tong University (CN)
  • Shanghai Institute of Nutrition and Health (CN)
  • St. Jude Children's Research Hospital (US)
  • 4CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Lingang Laboratory, Shanghai, China.
Corresponding author
  • Zhang, Zhe
  • Wang, Zhaoyang
  • Shen, Jianfeng
ORCID
Venue
Cancer Immunology Research
Publisher
American Association for Cancer Research (AACR)
Published
2023-09-26
Volume
11
Issue
12
Pages
1671-1687
ISSN
  • 2326-6066 (ISSN-L)
  • 2326-6074
DOI
10.1158/2326-6066.cir-23-0083
OpenAlex
W4387088612
Cited by
22
References
3
Citations by year
2026: 8 · 2025: 9 · 2024: 4 · 2023: 1
FWCI
5.30
Type
journal article
Language
en
Open access
closed
Locations
  • Cancer Immunology Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81972667)
  • National Key Research and Development Program of China (2021YFC2701103)
Topics
  • Health Sciences › Medicine › Ophthalmology › Ocular Oncology and Treatments
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
uveal melanoma, alternative splicing, neoantigens, SF3B1, long-read sequencing, nanopore sequencing, novel isoforms, cancer immunotherapy, interferon-gamma, T cell-mediated tumor killing
MeSH terms
RNA Splicing Factors, Uveal Melanoma, Adult, Humans, Melanoma, Phosphoproteins, Uveal Neoplasms, Alternative Splicing

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