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  • Acknowledgements br This work was

    2019-10-15

    Acknowledgements
    This work was supported by the National Natural Science Foundation of China (21890742, 21735006) and AZD-5991 Chinese Academy of Sciences.  Experimental Cell Research xxx (xxxx) xxx–xxx
    Appendix A. Supplementary data
    References
    Contents lists available at ScienceDirect
    Molecular Immunology
    journal homepage: www.elsevier.com/locate/molimm
    A new strategy for enhancing antitumor immune response using dendritic T AZD-5991 loaded with chemo-resistant cancer stem-like cells in experimental mice model
    Nahla E. El-Ashmawya, Enas A. El-Zamaranyb, Mohamed L. Salemc,d, Eman G. Khedra, Amera O. Ibrahima, a Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt b Clinical Pathology Department, Faculty of Medicine, Tanta University, Egypt c Zoology Department, Faculty of Science, Tanta University, Egypt d Center of Excellence in Cancer Research, Tanta University, Tanta, Egypt
    Keywords:
    Cancer stem cells
    Dendritic cells
    Interferon gamma
    Cisplatin
    Solid Ehrlich carcinoma
    Immunotherapy 
    Background and aim: Cancer stem cells (CSCs) are rare cell population present in the tumor bulk that are thought to be the reason for treatment failure following chemotherapy in terms of their intrinsic chemo-resistance. Our study aimed to develop an effective therapeutic strategy to target chemo-resistant cancer stem – like cells po-pulation in solid Ehrlich carcinoma (SEC) mice model using dendritic cells (DCs) loaded with enriched tumor cells lysate bearing CSC-like phenotype as a vaccine.
    Materials and methods: Ehrlich carcinoma cell line was exposed to different concentrations of cisplatin, doxor-ubicin, or paclitaxel. Drug treatment that resulted in drug surviving cells with the highest expression of CSCs markers (CD44+/CD24−) was selected to obtain enriched cell cultures with resistant CSCs population. Dendritic cells were isolated from mice bone marrow, pulsed with enriched CSC lysate, analyzed and identified (CD11c, CD83 and CD86). SEC-bearing mice were treated with loaded or unloaded DCs either as single treatment or in combination with repeated low doses of cisplatin. IFN- γ serum level and p53gene expression in tumor tissues were determined by ELISA and real-time PCR, respectively.
    Results and conclusion: The results revealed that vaccination with CSC loaded DCs significantly reduced tumor size, prolonged survival rate, increased IFN-γ serum levels, and upregulated p53gene expression in SEC bearing mice. These findings were more evident and significant in the group co-treated with CSC-DC and cisplatin rather than other treated groups. This study opens the field for combining CSC-targeted immunotherapy with repeated low doses chemotherapy as an effective strategy to improve anticancer immune responses.
    1. Introduction
    Conventional chemotherapy is one of the most common treatment options for cancer. Unfortunately, the efficacy of chemotherapy is limited and tumor recurrence may occur after treatment. Tumor im-munotherapy has been reported to be effective and represent a pro-mising strategy which acts as a trigger for mobilizing the body’s im-mune cells to attack tumor cells (Salem et al., 2015). Several experimental studies illustrated the presence of a very small percentage of tumor resistant self-renewing cells in the heterogeneous cells populations of the tumor mass that are able to escape conventional therapy and regenerate the tumor bulk (Nandi et al., 2008; Dallas et al., 2009; Lopez-Ayllon et al., 2014). This cell population are known as
    Corresponding author.
    E-mail address: [email protected] (A.O. Ibrahim). 
    cancer stem cells (CSCs) or cancer-initiating cells which are char-acterized by unique properties such as self-renewal, capability of in vivo tumorigenesis, metastasis, and high resistance to chemotherapy and apoptosis (Ma et al., 2010; Lu et al., 2015).