Cytokine-induced killer cells (CIK) cells are a group of immune effector cells featuring a mixed T- and natural killer (NK) cell-like phenotype. They are generated by ex vivo incubation of human peripheral blood mononuclear cells (PBMC) or cord blood mononuclear cells with interferon-gamma (IFN-γ), anti-CD3 antibody, recombinant human interleukin (IL)-1 and recombinant human interleukin (IL)-2.
Typically, immune cells detect major histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine release, causing lysis or apoptosis. However, CIK cells have the ability to recognize infected or even malignant cells in the absence of antibodies and MHC, allowing for a fast and unbiased immune reaction. This is of particular importance as harmful cells that are missing MHC markers cannot be tracked and attacked by other immune cells, such as T-lymphocytes. As a special feature, terminally differentiated CD3+CD56+ CIK cells possess the capacity for both MHC-restricted and MHC-unrestricted anti-tumor cytotoxicity. These properties, inter alia, rendered CIK cells attractive as a potential therapy for cancer and viral infections.
A new subclass of NK cells have been created both in vitro and in vivo. These NK cells referred to as cytokine induced memory-like natural killer cells are induced using cytokines, most commonly a mix of IL-12, IL-15, and IL-18. These NK cells are activated by these cytokines to stimulate an infection and induce an adaptive immune response. If cocultured with target cells such as tumor targets, these NK cells have memory-like abilities and are more adapt and effective at mounting a defense.
Nomenclature
They were given the name “cytokine-induced killer” because cultivation with certain cytokines is mandatory for the maturation into terminally differentiated CIK cells. Several sources also call them natural killer cell-like T cells due to their close relationship to NK cells. Others propose to classify CIK cells as subset of NKT cells.
Mechanism
It has been shown that lymphocytes, when exposed to interferon-gamma, anti-CD3 antibody, interleukin-1 and interleukin 2, are capable of lysing fresh, non-cultured cancer cells, both primary and metastatic. CIK cells respond to these lymphokines, particularly IL-2, by lysing tumor cells that were already known to be resistant to NK cell or LAK cell activity.
Peripheral blood mononuclear cells or cord blood mononuclear cells are extracted from either peripheral blood or cord blood, e.g. by simple blood draw. Extracted cells are ex-vivo exposed to interferon-gamma, anti-CD3 antibody, interleukin-1 and interleukin-2 in a time-sensitive schedule. These cytokines strongly stimulate the proliferation and maturation into CIK cells. After completed maturation CIK cells are transfused to the donor in autologous settings or to different recipients in allogeneic settings. Furthermore, it has been shown that CIK cells have a relevant expression of FcγRIIIa (CD16a), which can be exploited in combination with clinical-grade mAbs to redirect their activity in an antigen-specific manner. Indeed, the engagement of CD16a on CD3+CD56+ cells led to a potent antibody-dependent cell–mediated cytotoxicity (ADCC) both in vitro and in vivo against ovarian cancer.,. Recently, it has been demonstrated the efficacy of a combined approach (CIK + Cetuximab) against triple negative breast cancer (TNBC), an aggressive tumor that still requires therapeutic options. Different primitive and metastatic TNBC cancer mouse models were established in mice, and the treatment CIK cells plus cetuximab significantly restrained primitive tumor growth in mice, either in patient-derived tumor xenografts or MDA-MB-231 cell line models. Moreover, this approach almost completely abolished metastasis spreading and dramatically improved survival. The antigen-specific mAb favored tumor and metastasis tissue infiltration by CIK cells, and led to an enrichment of the CD16a+ subset. Data highlight the potentiality of this novel immunotherapy strategy where a nonspecific cytotoxic cell population can be converted into tumor-specific effectors with clinical-grade antibodies, thus providing not only a therapeutic option for TNBC but also a valid alternative to more complex approaches based on chimeric antigen receptor-engineered cells.
Function
The mechanism of CIK cells is distinctive from that of natural killer cells or LAK cells because they can lyse cells that NK cells and LAK cells cannot.