• Exosomal Non-Coding RNAs as Key Regulators of PD-L1-Mediated Immune Escape in Colorectal Cancer
  • Elham Kamalkazemi,1 Nasser Hashemi Goradel,2 Fatemeh Badipa,3 Masomeh Amani Dolama,4 Effat Alizadeh,5,*
    1. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
    2. Department of Medical Biotechnology, Maragheh University of Medical Sciences, Maragheh, Iran
    3. Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
    4. Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
    5. Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran


  • Introduction: Still, colorectal cancer (CRC) is considered to be the leading cause of cancer-related mortality worldwide despite the many attempts that have been made to prevent its progression. The PD-1/PD-L1 signaling pathway plays a crucial role in local immunosuppression within the tumor microenvironment. PD-L1 is frequently found in human cancers and on activated T cells. When PD-L1 binds to its receptor, inhibits anti-tumor immune responses by blocking T-cell activation signals. Recent advances have highlighted the role of exosomes (small extracellular vesicles) as key mediators of intercellular communication, transferring various bioactive molecules, including proteins, metabolites, amino acids, and non-coding RNAs. Such exosomal non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, can play a key role in CRC tumorigenesis and metastasis within the tumor microenvironment by regulating PD-1/PD-L1 signaling. Therefore, they can be used as potential novel cancer biomarkers and immunotherapeutic targets. This review article explores the association of exosomal microRNAs and the PD-1/PD-L1 signaling pathway in CRC.
  • Methods: We performed a comprehensive search in the PubMed and Google Scholar databases using keywords such as CRC, exosome, microRNA, PD-L1, and immunotherapy to find original research articles that investigated the function of exosomal microRNAs in modulating the PD-1/PD-L1 pathway in CRC.
  • Results: Exosomal miR-17-5p fromCRC stem cells inhibits SPOP, an E3 ubiquitin ligase, which leads to the stabilization of PD-L1 and a decrease in anti-tumor immune responses. This process promotes the proliferation of CRC cells and reduce the infiltration of CD8+ T-cells. Additionally, exosomal miR-372-5p from CRC cells diminish PTEN levels, which activates the PI3K/AKT/NF-κB signaling pathway, resulting in increased PD-L1 expression in macrophages and tumor cells. Exosomal circEIF3K derived from cancer-associated fibroblasts enhances the progression ofCRC through the miR-214/PD-L1 pathway. Exosomes derived from tumor cells containing lncRNA KCNQ1OT1 facilitate immune evasion in CRC by targeting the miR-30a-5p/USP22 pathway, which leads to the suppression of PD-L1 and dampens the response of CD8+ T-cells.
  • Conclusion: Exosomal Non-coding RNAs play a pivotal role in modulating PD-L1 expression in CRC, enabling tumor immune evasion and progression. The findings of this work may help control and eradication of CRC using exsosomal RNA contents.
  • Keywords: Colorectal cancer, Exosome, Non-coding RNAs, PD-1/PD-L1 signaling, Immune scape