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N6-methyladenosine reader protein IGF2BP1 suppresses CD8 + T cells-mediated tumor cytotoxicity and apoptosis in colon cancer

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Abstract

Tumor immune escape is an important manner for colon cancer to escape effective killing by immune system. Currently, the immune checkpoint PD-1/PD-L1-targeted immunotherapy has emerged as a promising therapeutic strategy in colon cancer. Here, present work aims to investigate the biological function of N6-methyladenosine (m6A) reader insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) in regulating colon cancer’s immune escape and CD8 + T cells-mediated tumor cytotoxicity and apoptosis. Results illustrated that IGF2BP1 was closely correlated to the colon cancer patients’ poor clinical outcome. Functionally, upregulation of IGF2BP1 suppressed the CD8+ T-cells mediated antitumor immunity through reducing their tumor cytotoxicity. Mechanistically, MeRIP-Seq revealed that programmed death ligand 1 (PD-L1) mRNA had a remarkable m6A modified site on 3’-UTR genomic. Moreover, PD-L1 acted as the target of IGF2BP1, which enhanced the stability of PD-L1 mRNA. Overall, these results indicated that IGF2BP1 targeted PD-L1 to accelerate the immune escape in colon cancer by reducing CD8 + T cells-mediated tumor cytotoxicity in m6A-dependent manner. The findings demonstrate the potential of m6A-targeted immune checkpoint blockade in colon cancer, providing a novel insight for colon cancer immune escape and antitumor immunity in further precise treatment.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Shenzhen University General Hospital, Shenzhen, 518055, China

    Yao Peng, Zhili Zhang, Gongli Yang, Zhongming Dai, Xunchao Cai, Zhenyu Liu, Qian Yun & Long Xu

  2. Shenzhen University Clinical Medical Academy, Shenzhen, 518055, China

    Yao Peng, Zhili Zhang, Xunchao Cai & Long Xu

  3. Shenzhen University International Cancer Center, Shenzhen, 518055, China

    Yao Peng, Zhili Zhang & Long Xu

Authors
  1. Yao Peng
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  2. Zhili Zhang
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  3. Gongli Yang
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  4. Zhongming Dai
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  5. Xunchao Cai
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  6. Zhenyu Liu
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  7. Qian Yun
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  8. Long Xu
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Contributions

Yao Peng，Zhili Zhang performed the assays. Gongli Yang，Zhongming Da，Xunchao Cai，Zhenyu Liu，Qian Yun wrote the main manuscript and prepared Figs. 1, 2, 3, 4, 5, 6 and 7. Long Xu was responsible for the funding. All authors reviewed the manuscript.

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Correspondence to Long Xu.

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The authors declare no competing interests.

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Both human and animal studies have been approved by the Ethical Committee of Shenzhen University General Hospital. Written informed consent was obtained from each patient.

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Peng, Y., Zhang, Z., Yang, G. et al. N6-methyladenosine reader protein IGF2BP1 suppresses CD8 + T cells-mediated tumor cytotoxicity and apoptosis in colon cancer. Apoptosis 29, 331–343 (2024). https://doi.org/10.1007/s10495-023-01893-7

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  • DOI: https://doi.org/10.1007/s10495-023-01893-7

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