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Background <p>Microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC) patients are the dominant population in immune checkpoint blockade treatments, while more than half of them could not benefit from single-agent immunotherapy. We tried to identify the biomarker of MSI-H CRC and explore its role and mechanism in anti-PD-1 treatments. Tumor-specific MHC-II was linked to a better response to anti-PD-1 in MSI-H CRC and CD74 promoted assembly and transport of HLA-DR dimers.</p> Methods <p>The characteristic gene was screened by data analysis of single-cell and bulk transcriptome sequencing from public datasets. MSI-H CRC cells co-cultured with peripheral blood mononuclear cells and syngeneic model in C57BL/6 mice were performed to detect the sensitivity to anti-PD-1 treatments respectively.</p> Results <p>ANXA10 was identified as a characteristic gene of MSI-H CRC and its expression was obviously greater in MSI-H than MSS CRC. ANXA10 significantly sensitized MSI-H CRC to anti-PD-1 treatments in vitro and in vivo. Specifically, ANXA10 promoted HLA-DR dimers in and on the surface of MSI-H CRC by increasing CD74 expression. Besides, this work demonstrated that ANXA10 contributed to better clinical benefits with anti-PD-1 therapy in MSI-H CRC patients.</p> Conclusions <p>Our results provided a novel molecular marker ANXA10 to identify benefit population of MSI-H CRC for improving efficacy of anti-PD-1 and contributed to selection of treatment strategies.</p>

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ANXA10 sensitizes microsatellite instability-high colorectal cancer to anti-PD-1 immunotherapy via assembly of HLA-DR dimers by regulating CD74

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月10日

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  • Yiting Sun,
  • Bowen Yang,
  • Ti Wen,
  • Xiaoyu Guo,
  • Danni Li,
  • Ruichuan Shi,
  • Fuqiang Zhang,
  • Dongni Wang,
  • Ce Li,
  • Xiujuan Qu

摘要

Background

Microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC) patients are the dominant population in immune checkpoint blockade treatments, while more than half of them could not benefit from single-agent immunotherapy. We tried to identify the biomarker of MSI-H CRC and explore its role and mechanism in anti-PD-1 treatments. Tumor-specific MHC-II was linked to a better response to anti-PD-1 in MSI-H CRC and CD74 promoted assembly and transport of HLA-DR dimers.

Methods

The characteristic gene was screened by data analysis of single-cell and bulk transcriptome sequencing from public datasets. MSI-H CRC cells co-cultured with peripheral blood mononuclear cells and syngeneic model in C57BL/6 mice were performed to detect the sensitivity to anti-PD-1 treatments respectively.

Results

ANXA10 was identified as a characteristic gene of MSI-H CRC and its expression was obviously greater in MSI-H than MSS CRC. ANXA10 significantly sensitized MSI-H CRC to anti-PD-1 treatments in vitro and in vivo. Specifically, ANXA10 promoted HLA-DR dimers in and on the surface of MSI-H CRC by increasing CD74 expression. Besides, this work demonstrated that ANXA10 contributed to better clinical benefits with anti-PD-1 therapy in MSI-H CRC patients.

Conclusions

Our results provided a novel molecular marker ANXA10 to identify benefit population of MSI-H CRC for improving efficacy of anti-PD-1 and contributed to selection of treatment strategies.