Document Type : Original Article
Stem Cells Laboratory, National Center for Biotechnology, Korgalzhyn Highway 13/5, Nur-Sultan, Kazakhstan
International School of Medicine, Caspian University, 85A Dostyk Street, Almaty, Kazakhstan
School of Sciences and Humanities, Nazarbayev University, 53 Kabanbay Batyr Avenue, Nur-Sultan, Kazakhstan
Introduction: Colorectal cancer remains a leading cause of cancer-related mortality worldwide. Cancer immunotherapy involves autologous tumor-derived antigen-loaded Dendritic Cells (DCs) that activate potent antitumor immunity. Cytokine-Induced Killer (CIK) cells are a heterogeneous population of anti-tumor cytotoxic CD8+ T-cells. Cancer immunotherapy using a combination of CIK cells with DCs vaccines is a promising strategy. We investigated some of the latest developments in the DCs vaccination field, with a special emphasis on strategies to prepare highly immunogenic tumor cell antigens to load and to activate DCs. In this context, we applied the effects of immunogenic treatment
modalities (heat shock) and four potent inducers of immunogenic cell death and apoptosis (mitoxantrone, oxaliplatin, 5 fluorouracil, and staurosporine) on DCs biology and their employment in DC-based activation of CIK cells.
Materials and Methods: DCs were generated from bone marrow cells using granulocyte-macrophage colony-stimulating factor and Interleukin (IL)-4. CIK cells were expanded by interferon-gamma (IFN-γ), anti-CD3 monoclonal antibody, and IL-2 stimulation. The cytotoxic activity of CIK cells against CMT-93 cancer cells was assessed by MTT assay. IFN-γ production of CIK cells was examined by ELISA.
Results: Coincubation of untreated DCs with CIK cells significantly induces antitumor immunity of CIK cells. Mature DCs loaded by polyethylene glycol with mitoxantrone-oxaliplatin-induced apoptotic tumor cells stimulate greater cytotoxicity of CIK cells compared to DCs loaded with staurosporine, oxaliplatin- and 5-fluorouracil-inactivated tumor cell antigens, whole tumor lysates, and total tumor RNA in CMT-93 cells.
Conclusions: Heat shock and mitoxantrone-oxaliplatin-treatment are the best approaches for cancer cell antigens preparation for DC-induced CIK cells activation.