6.4.3 Biological Characteristics of CIK Cells
Intensive and strict studies on the immune phenotype of CIK cells have been conducted.CIK cells,which are a heterogeneous cell population, comprise CD3+CD56+, CD3+CD56-, and CD3-CD56+cells.CD3+CD56+ cells, which are derived from CD3+CD56- T cells, are also called natural killer T(NKT) cells and are primarily responsible for non-major histocompatibility complex (MHC)-restricted antitumor activity.Furthermore, this subset co-expresses CD2, T cell receptor (TCR) αβ,and CD8, but not CD16.In addition, CD3+CD56+ cells bear the CD27+CD28- or CD27-CD28-phenotype because they belong to terminally differentiated T-cell populations, whereas CD3+CD56-cells are subjected to early differentiation and mainly express the CD27+CD28+ and CD62L+ phenotypes.Meanwhile, CD3+CD56-cells also express CD4, CD8, and TCRαβ.CD3-CD56+ cells behave similarly to conventional natural killer (NK) cells and express classical NK-cell receptors.In addition to these markers, CIK cells express CD45RA, C-C chemokine receptor (CCR)7, CD11a, macrophage inflammatory protein 1a, perforin, and Fas ligand [110,111].
The immune function-related genes of CIK cells have also been described in recent years.A number of studies have presented that the immune function-related genes of CIK cells are changed under tumor cell stimulation.For example, upon stimulation by acute myelocytic leukemia (AML)cell lines, a CD3+CD56+ subset of CIK cells highly express various immune function-related genes such as IFN-γ, TNF-α, the cytokine receptor genes IL-7R and IL-12Rβ2, the chemokine and chemokine receptor genes C-C chemokine ligand (CCL)4, CCL5, chemokine (C-X-C motif)receptor (CXCR)3, and CCR1, and the genes encoding granzyme B and caspase-1.With the exception of these genes, the expression levels of many other genes were up-regulated and those of 7 genes were down-regulated in CIK cells stimulated by AML cells.Furthermore, the genes encoding IFN-γ, GM-CSF, IL-4, IL-8, IL-2Rα, IL-2Rβ, IL-4R, IL-12Rβ, chemokines, chemokine receptors, and TNF were highly expressed in CIK cells under stimulation by acute lymphoblastic leukemia (ALL) cells.Based on these findings, CIK cells may act consistently with T helper 1 and T cytotoxic 1 cell polarization upon stimulation by tumor cells.The expression of related genes in CIK cells seems similar even under stimulation by different tumor cells [112].(https://www.daowen.com)
Currently, the migration and homing of CIK cells are being investigated.More and more evidence from animal models has indicated that CIK cells, similar with conventional T cells, can migrate to tumors, tumor-draining lymph nodes, and spleen tissues.The distribution and order of flow for CIK cells were related to the immune properties of the cells, the blood supply, and the expression of certain specific chemokines and chemokine receptors for the tumor.The detailed mechanism and efficacy of CIK cell trafficking might involve: (1) the up-regulation of specific receptors or ligands on the tumor or tumor-draining lymph nodes to promote the homing, adhesion, and infiltration of CIK cells and (2) the chemokines, chemokine receptors, selectins, and adhesion molecules expressed on CIK cells that are involved in the migration of CIK cells across the endothelium.On the contrary, CIK cells infiltrate normal target tissues to a much smaller extent or transiently for a longer time.This result was confirmed by another animal study.CIK cells are effective against Fas ligand-positive malignant cells and cells with multidrug resistance.It has been observed that a population of CIK cells migrated to tumor sites by 72 h after infusion and remained detectable at these sites for an additional 9 days.Meanwhile, transplanted tumor cells in mice could be significantly destroyed by these CIK cells [113,114].
Thus far, numerous studies have demonstrated that CIK cells have potent cytotoxic activities against various tumors such as human leukemia, ovarian cancer, lung cancer, liver cancer, cervical cancer, and colorectal cancer; among CIK cells, CD3+CD56+ cells have the most potent MHC-unrestricted cytolytic effect.The antitumor mechanisms of CIK cells include effector cell-target cell contacts through binding of the surface adhesion molecule leukocyte function-associated antigen-1 (LFA-1) on CIK cells to LFA-1 ligands expressed on most susceptible tumor cells, thereby leading to cytotoxicity against tumor cells; the cell signaling pathway involving the binding and activity of NK-cell receptors to their ligands, which are highly expressed on tumor cells, resulting in CIK cell activation that leads to degranulation and cytotoxicity against tumor cells; and the induction of tumor cell apoptosis by Fas ligand via the Fas signaling pathway.In addition, applications in an animal model suggested that in vivo antitumor effects against various hematopoietic and solid tumors occurred after the infusion of CIK cells.A preclinical study reported that the survival of severe combined immunodeficient mice injected with human lymphoma cells could be significantly prolonged after receiving CIK cell infusion [115].