Abstract
Cytokine-induced killer cells (CIK) have been used in clinic for adoptive immunotherapy in a variety of malignant tumors and have improved the prognosis of cancer patients. However, there are individual differences in the CIK cell preparations including the obvious differences in the ratio of effector CIK cells among different cancer patients. Infusion of such heterogeneous immune cell preparation is an important factor that would affect the therapeutic efficacy. We report here the enrichment and expansion of CD8+ cells from CIK cells cultured for one week using magnetic activated cell sorting (MACS). These enriched CD8+ CIK cells expressed T cell marker CD3 and antigen recognition receptor NKG2D. Phenotypic analysis showed that CD8+ CIK cells contained 32.4% of CD3+ CD56+ natural killer (NK)-like T cells, 23.6% of CD45RO+ CD28+, and 50.5% of CD45RA+ CD27+ memory T cells. In vitro cytotoxic activity assay demonstrated that the enriched CD8+ CIK cells had significant cytotoxic activity against K562 cells and five ovarian cancer cell lines. Intriguingly, CD8+ CIK cells had strong cytotoxic activity against OVCAR3 cells that has weak binding capability to NKG2D. Flow cytometry and quantitative RT-PCR analysis revealed that OVCAR3 cells expressed HLA-I and OCT4 and Sox2, suggesting that CD8+ CIK cells recognize surface antigen via specific T cell receptor and effectively kill the target cells. The results suggest that transplantation of such in vitro enriched and expanded OCT4-specific CD8+ CIK cells may improve the specific immune defense mechanism against cancer stem cells, providing a novel avenue of cancer stem cell targeted immunotherapy for clinical treatment of ovarian cancer.
Highlights
Cytokine-induced killer cells (CIK) are a type of polyclonal killer T cells that are activated by interferon-gamma (IFN-γ) and CD3 antibody
The binding of NKG2 with NKG2D ligands (NKG2DL) promotes the release of perforin and granzyme B leading to subsequent apoptosis of CIK target cells [7,8,9,10]
These results showed that these ovarian cancer cells expressed different NKG2D ligands at different levels
Summary
Cytokine-induced killer cells (CIK) are a type of polyclonal killer T cells that are activated by interferon-gamma (IFN-γ) and CD3 antibody. Phenotypic characterization and anticancer capacity of CD8+ CIK cells cells with CD3+ CD56+ phenotype [5, 6] These CIK effector cells express NKG2D receptor and recognize cancer cell surface NKG2D ligands (NKG2DL), including MICA, MICB and ULBPs in HLA-unrestricted manner. Clinical studies have revealed that CIK cell infusion significantly benefits cancer patients with MICA/B+ expression [11,12,13]. The binding of TCR with HLA-I bound antigen peptides on the surface of target cells is able to transduce signals to generate HLA-restricted function of CIK cells [14, 15]. CD8+ CIK cells are believed to be a class of bifunctional cells that have both TCR and NKG2D antigen recognition receptors and are capable of exerting immune killing effects via HLA restricted and unrestricted mechanisms. We hypothesize that transplantation of CD8+ CIK cells that are sorted from conventional CIK culture and expanded in vitro might significantly improve clinical outcomes
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