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SDCBP modulates tumor microenvironment, tumor progression and anti-PD1 efficacy in colorectal cancer

Cancer Gene Therapy (2024)Cite this article

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Abstract

Anti-programmed cell death 1 (aPD1) therapy has yielded limited success in patients with colorectal cancer (CRC). Syndecan binding protein (SDCBP), encodes a PDZ domain-containing protein that is essential for cellular processes, including cell adhesion, migration, and signal transduction. Here, we investigated the effect of SDCBP on tumor progression, immunotherapy, and the tumor microenvironment (TME) in CRC. High expression of SDCBP is associated with non-response to immunotherapy and correlated with poorer disease-free survival (DFS) in CRC patients. Inhibiting SDCBP by transfecting shRNA or using its inhibitor zinc pyrithione (ZnPT) hindered proliferation and metastasis while enhancing the efficacy of aPD1 treatment in a mouse xenograft model and liver metastasis model. The TME of CRC was significantly altered following ZnPT treatment characterized by a reduced amount of M2 macrophages and a heightened percentage of M1 macrophages. The co-culture system of CRC cells and macrophages provided evidence that SDCBP silencing promoted the repolarisation of M2 macrophages into M1. SDCBP promotes the proliferation, metastasis, and immunotherapy resistance of CRC. Thus, ZnPT represents an effective SDCBP inhibitor and exhibits considerable potential for combination with aPD1 to enhance immunotherapy efficacy.

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Fig. 1: SDCBP promotes the tumor progression and immunotherapy resistance of CRC.
Fig. 2: ZnPT delays CRC progression and enhances the efficacy of PD-1 blockade through suppression of SDCBP expression.
Fig. 3: The combination of ZnPT and aPD1 effectively impedes the metastasis of CRC.
Fig. 4: ZnPT treatment alters the immune landscape of the CRC microenvironment.
Fig. 5: SDCBP deficiency leads to a decline in M2 macrophages infiltrating accompanied by an increase in M1 macrophages in the TME of CRC.
Fig. 6: Co-culture of SDCBP knockdown CRC cells and macrophages shifts the immune phenotype from M2 macrophage polarization to M1.

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Data availability

All data analyzed and generated in this study are included in this published article and its supplementary information files. Other data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82203098) and Health and Family Planning Scientific Research Project of Pudong New Area Health Committee (No. PW2022E-02).

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  1. These authors contributed equally: Jiahua Yu, Shijun Yu.

Authors and Affiliations

  1. Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China

    Jiahua Yu, Shijun Yu, Jin Bai, Yong Gao & Yandong Li

  2. Department of Colorectal Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China

    Zhe Zhu

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Contributions

Yandong Li, Yong Gao, and Zhe Zhu designed and supervised the study; Jiahua Yu and Shijun Yu performed most of cell and animal experiments and analyzed the data; Jin Bai assisted cell biology experiments; Jiahua Yu and Yandong Li wrote the manuscript. All authors have read and approved this final manuscript.

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Correspondence to Zhe Zhu, Yong Gao or Yandong Li.

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The study obtained approval from the Medical Ethics Committees of Shanghai East Hospital. All animal studies followed the guidelines approved by the Animal Experimentation Ethics Committee of Shanghai East Hospital, Tongji University.

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Yu, J., Yu, S., Bai, J. et al. SDCBP modulates tumor microenvironment, tumor progression and anti-PD1 efficacy in colorectal cancer. Cancer Gene Ther (2024). https://doi.org/10.1038/s41417-024-00758-8

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