NK cells, also known as natural killer cells, are derived from bone marrow lymphoid stem cells that depend on the bone marrow and thymic microenvironment for their differentiation and development and are mainly found in the bone marrow, peripheral blood, liver, spleen, lung and lymph nodes, producing pro-inflammatory cytokines and killing virally infected cells or cancer cells. NK cells have a broad spectrum of anti-tumor effects without showing tumor-killing specificity or MHC restriction and are particularly important when other immune cells (e.g. T and B cells) in the body are depressed. NK cell-mediated immunotherapy has emerged as a safe and effective therapy.
A variety of sources of therapeutic NK cells are currently being tested in the clinic, including autologous NK cells and alternative NK cells. The main sources of alternative NK cells are cord blood, stem cell-derived, cytokine-induced memory-like, and chimeric antigen receptor (CAR). Of these, primary NK cells are not ideal substrates for generating CAR cell products due to the challenges faced during cell isolation, transduction and expansion. As a result, current clinical trials of CAR-NK cells are focused on products of stem or progenitor cell origin.
Two Mechanisms of NK Cells Against Tumors
Missing-self
In 1986, Karre proposed the missing-self hypothesis, arguing that NK cells search for and attack abnormal cells lacking self (mainly referring to MHC-I). In a healthy state, NK cell surface inhibitory receptors recognize its own MHC class I molecules conduct inhibitory signals and protect the body from NK cell attacks. When virus infection or tumor occurs, the level of MHC class I molecules on the surface of target cells is down-regulated, resulting in the weakening of inhibitory signals, thereby inducing the activation of NK cells. NK cells can recognize and respond to cells of this missing-self phenotype, and eventually lead to lysis of target cells. Therefore, NK cells have therapeutic potential in situations where T cells fail to recognize cancer cells due to MHC-I downregulation.
Antibody-dependent Cell-mediated Cytotoxicity (ADCC)
ADCC means that the Fab segment of an antibody binds to the antigenic epitope of virus-infected cells or tumor cells, and its Fc segment binds to the FcR on the surface of killer cells (NK cells, macrophages, etc.), mediating killer cells to directly kill target cells. There are 3 mechanisms of action:
1) Perforin and granzyme pathways of action
Perforin is a cytotoxic substance stored in cytoplasmic granules and has a biological effect similar to that of the complement membrane attack complex. In the presence of calcium ions, it can form a multimeric perforin "pore" in the target cell membrane, allowing water electrolytes to enter the cell rapidly, leading to cell disintegration and destruction. Granzymes are serine proteases that follow the "pore" formed by the perforin in the target cell membrane to enter the cell and cause apoptosis by activating apoptosis-related enzyme systems.
2) Fas and FasL action pathway
Activated NK cells can express FasL on their surface. When FasL expressed by NK cells binds to the corresponding receptor Fas (CD94) on the surface of target cells, it forms a Fas trimer on the surface of the target cells, which causes the intracytoplasmic death domain to cluster together, and the latter binds to the Fas-associated death domain protein (FADD), which in turn activates caspase8 through recruitment and activation. This leads to the death of the target cell through a caspase cascade reaction.
3) TNF-α and TNFR-I pathways of action
TNF-α acts similarly to FasL in that they bind to the corresponding receptor on the surface of the target cell, the type I TNF receptor (TNFR-I), causing it to form a TNF-R trimer, which leads to the clustering of the intracytoplasmic death domain and the recruitment of the death domain protein (FADD) binding, which in turn leads to cell death through the recruitment and activation of caspase8.
Advantages of NK Cell Immunotherapy
- Immune cell therapy is the fourth treatment after surgery, chemotherapy and radiotherapy. NK cell therapy combined with radiotherapy and chemotherapy can effectively remove tumor cells that cannot be completely removed by surgery.
- NK cell therapy combined with radiotherapy and chemotherapy can improve the efficacy of radiotherapy and chemotherapy and reduce side effects.
- For advanced cancer patients who are not suitable for surgery or radiotherapy and chemotherapy, NK cell therapy is a better choice.
- Regular use of NK cell therapy after surgery can prevent cancer recurrence and metastasis.
- Relieve cancer pain, improve sleep, improve the quality of life of patients, and prolong the life cycle of patients.
- For sub-healthy people, NK cell therapy can reduce the risk of cancer.
NK cell therapy is gradually becoming a very promising field of clinical research, but there are still many challenges to be solved, such as immunosuppression in TME, lack of growth factors necessary for NK cell proliferation and survival, etc. Future therapeutics must not only target NK cells to tumor cells, but also maximize the effectiveness of therapeutic NK cell products by increasing the persistence of these lymphocytes in vivo.
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