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<p>Intron retention (IR) is an underexplored source of alternative neoantigens in cancer. Unlike mutation-derived neoantigens, IR-derived neoantigens can arise even in malignancies with low tumour mutational burden (TMB), such as microsatellite-stable colorectal cancer (MSS-CRC), making them a potentially important source of tumour antigens. Here, we provide experimental evidence that IR-derived neoantigens are expressed in tumours and are recognized by T cells, with approximately 30% of predicted epitopes eliciting measurable CD8<sup>+</sup> T cell responses. We applied a bioinformatics pipeline to RNA sequencing data from 23 CRC patients, identifying 49 patient-specific and 24 shared IR-derived neoantigens, the latter present in ~ 30% of the cohort. Notably, most shared neoantigens exhibited high binding affinity to the predominant HLA alleles, highlighting their potential as broadly targetable vaccine candidates. Together, these findings establish IR-derived neoantigens as a validated and clinically relevant class of tumour antigens, expanding opportunities for personalized and off-the-shelf immunotherapies in CRC and other low-TMB cancers.</p>

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Identification of immunogenic neoantigens from intron retention in colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月9日

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  • Thamizhanban Manoharan,
  • Brandon Bing Rui Kee,
  • Cyrus Zai Ming Cheng,
  • Malcolm Kaiheng Choy,
  • Bei En Siew,
  • Wai-Kit Cheong,
  • Kai-yin Lee,
  • Ian Jse-Wei Tan,
  • Bettina Lieske,
  • Choon Kong Yap,
  • Iain Bee Huat Tan,
  • Ker-Kan Tan,
  • Kar Tong Tan,
  • Gloryn Chia

摘要

Intron retention (IR) is an underexplored source of alternative neoantigens in cancer. Unlike mutation-derived neoantigens, IR-derived neoantigens can arise even in malignancies with low tumour mutational burden (TMB), such as microsatellite-stable colorectal cancer (MSS-CRC), making them a potentially important source of tumour antigens. Here, we provide experimental evidence that IR-derived neoantigens are expressed in tumours and are recognized by T cells, with approximately 30% of predicted epitopes eliciting measurable CD8+ T cell responses. We applied a bioinformatics pipeline to RNA sequencing data from 23 CRC patients, identifying 49 patient-specific and 24 shared IR-derived neoantigens, the latter present in ~ 30% of the cohort. Notably, most shared neoantigens exhibited high binding affinity to the predominant HLA alleles, highlighting their potential as broadly targetable vaccine candidates. Together, these findings establish IR-derived neoantigens as a validated and clinically relevant class of tumour antigens, expanding opportunities for personalized and off-the-shelf immunotherapies in CRC and other low-TMB cancers.