Nature review: Cancer immunotherapy "new power" - NK cell therapy.

Li Yuan NK cells are innoculation lymphocytes that produce inflammatory cytokines and can kill infected cells or cancer cells.
20 years ago, NK cell-mediated immunotherapy became a safe and effective treatment in patients with advanced leukemia.
, anti-cancer research on NK cells has grown exponentially and is now a major area of immunotherapy innovation.
development of NK cell therapy usually has two priorities: optimizing the source of therapeutic NK cells for over-transfer and enhancing the toxicity and persistence of NK cells.
In a review entitled "Exploring the NK cell platform for cancer immunotherapy" published on September 15th, two scientists from the University of Minnesota in the United States presented a variety of NK cell therapies targeting human cancer and ways to enhance NK cell activity in the body, and set the future direction for NK cell therapy research.
source: Nature Reviews Clinical OncologyNK cell anti-tumor NK cells have cytototoxic activity, function is most similar to CD8 T cells.
including the spleen, liver, secondary lymphatic organs, thymus, intestines, tonsils and uterus are all developmental sites of NK cells.
unlike B cells and T cells, NK cells do not express antigen receptors for sobody cell rearms, but rather for random combinations of activated and inhibited receptors.
the balance between stimulus and inhibition signals expressed through these different subjects allows NK cells to show response or tolerance to the target cells (Figure 1).
Figure 1 NK cells respond to viral infections and transformational cells by balancing signals (Source: Nature Reviews Clinical Oncology) NK cells have a variety of functions that can limit the growth and spread of cancer cells, or they can be guided by inflammatory covide factors in the tumor micro-environment (TME) to collect circulating NK cells to the site where the tumor occurs.
TME, NK cells can kill cancer cells through the "missing-self" mechanism.
activation of NK cells is inhibited by the binding of inhibited subjects to MHC-I (known in humans as HLA-I) molecules.
However, many cancer cells reduce the expression of MHC-I molecules to evade detection of CD8 T cells, and NK cells can identify and respond to this "missing-self" esogram cell, eventually leading to cleavage of the target cell (Figure 1).
, NK cells have therapeutic potential in cases where T cells cannot recognize cancer cells due to MHC-I reduction.
Antibody-dependent cell-mediated cytotoxicity (ADCC) is another key mechanism for NK cells to kill cancer cells, and NK cells identify and kill tumor cells that are monoantigenized by Fc-binding and monoantigen binding on the cell surface.
There is evidence that NK cell-mediated ADCC is an important mechanism for the success of therapeutic monoantigens (such as lyxi monoantigen and clexides) in patients with blood or solid cancer, demonstrating the great therapeutic potential of NK cells.
in addition to directly inducing cytotoxicity, NK cells also respond to transformed cells by producing inflammatory cytokines, including IFN gamma and TNF.
these multi-effect proteins not only enhance the response capacity of CD8 T cells, but also have effective anti-proliferation, anti-angiogenesty and apoptosis effect on cancer cells.
NK cell sources are currently clinically testing therapeutic NK cells from a variety of sources, including autobiographical NK cells and alternative NK cells, the latter including cord blood NK cells, stem cell-sourced NK cells, cytokine-induced memory-like NK cells, and chisellular antigens (CAR) NK cells.
, due to the challenges faced during cell separation, transduction and amplification, the original NK cells are not ideal substrates for producing CAR cell products.
, current clinical trials of CAR-NK cells are focused on products from stem cells or ancestral cell sources.
Table 1 Is an ongoing clinical trial of therapeutic NK cell products Source: Nature Reviews Clinical Oncology's methods for significantly increasing NK cytotoxicity and longevity are also being studied in clinical studies, including cytokine-based drugs, NK cell bridger molecules, and immuno checkpoint inhibitors.
NK cell activity in the body, cytokines IL-2 and IL-15 were identified as key cytokines to improve NK cell activity.
over the past 10 years, IL-15 has gradually replaced IL-2.
In preliminary studies on models of cancer homogenous mice such as melanoma, colorectal cancer, lymphoma and lung cancer, rIL-15 has good tolerance, regulating the amplification of NK cells and CD8 T cell populations, promoting tumor subsidion and reducing metastasis.
and rIL-15 can be used neither as a monotherapy nor as an adage for step cell therapy.
addition to rIL-15, there are several other methods of immunostulation using IL-15 that are being clinically tested (Figure 2).
2 ways to enhance the function of NK cell effectors (Source: Nature Reviews Clinical Oncology) Various immune escape mechanisms of NK cell bridger limit the binding degree of NK cells and tumor cells in the body, which is the main obstacle to the development of a wide range of effective NK cell therapy.
team has developed molecules that enable tumor-inferative NK cells to come into contact with tumor cells in an antigen-specific manner, increasing the natural cytotoxicity of these cells. The molecules developed by
are usually dual- or trisexual bridging proteins consisting of multiple antigen-targeted domains (usually scFvs), one domain targeting NK cell activation subjects, and the other binding to specific tumor-related antigens.
preclinical studies have shown that a variety of NK cell bridger molecules have effective anti-tumor effects.
currently, trisexual NK cell bridger therapy (TriNKET) with at least four target blood malignancies-related antigens is in its early stages of development.
although the number of clinically tested NK cell bridger therapies is small, many companies are developing similar products and are expected to enter clinical trials in the near future.
Table 2 Part NK Cell Convergence and NK Cell Directed Cytokine Therapy Clinical Oncology Immunosuppression TIGITTIGIT is an inhibitory subject of NK cell and T cell expression with Ig and ITIM domains.
TIGIT has been found to be expressed in human tumor-indaching NK cells.
in a variety of mouse models, inhibiting TIGIT reverses the depletion of NK cells and promotes NK cell-dependent anti-tumor immunity.
CD96 is similar to TIGIT, the study found that the level of inhibitory subject CD96 was higher on NK cells in tumor tissue than on NK cells in the tissue around the tumor.
, higher levels of CD96 expression on NK cells in hepatocellular carcinoma samples were associated with poor prognosis.
CD96 inhibitors are not currently in clinical trials, preclinical data suggest that the drug has the ability to inhibit experimental or spontaneous metastasis in multiple mouse models.
PD-1/L1 in preclinical models of PD-L1-tri-negative breast cancer and PD-L1-leukemia, NK cells have been identified as key media for PD-L1 antibody-induced cytotoxicity.
PD-1 expression is increased in NK cells in a variety of human cancer TME.
In addition, in several types of gastrointestinal cancer, higher levels of expression of PD-1 on NK cells were associated with poor prognostic prognosticity, indicating the rationality of PD-1 on targeted endogenous or pergenitous NK cells.
TIM3T cell immunoglobulin muclin inhibitor 3 (TIM-3) is another immuno-checkpoint protein with inhibitory properties, expressed by various white blood cells, including NK cells, and bind to the lithe Galectin-9 (expressed in human tumors).
in some studies, increased expression of TIM-3 on NK cells in lung cancer patients foreshadowed poor prognostics, and inhibition of TIM-3 in estosome NK cells enhanced their cytotoxicity and the production of IFN gamma.
inhibition of TIM-3 in NK cells in patients with advanced melanoma had similar results.
LAG-3 lymphocyte activation gene 3 (LAG-3) is an immune checkpoint subject that is widely expressed in a variety of white blood cells, including NK cells, activated T cells, B cells, and plasma cell-like dexterity cells, and can induce inhibitory signaling when combined with MHC CLASS II molecules.
preclinical evidence suggests that LAG-3 and PD-1 work together to regulate the immune escape of tumors, while LAG-3 inhibition enhances T-cell-mediated anti-cancer immunity.
, the role of LAG-3 in regulating NK cell-mediated anti-tumor immunity is not clear, and there is still a lack of research on the effects of LAG-3 inhibition on human NK cells.
research data from mouse NK cells show that LAG-3 plays an active role in mediated cytotoxicity of tumor cell line (suggesting that LAG-3 may act as an active subject in mouse NK cells), and further research is needed in this area.
, it is worth mentioning that traditional cell therapies from donor sources have a number of barriers and that "spot" products are critical to achieving widespread access to step-by-step NK cell therapies.
And NK cells are particularly suitable for the "spot" model, for the following reasons: (1) unlike T cells, NK cells do not necessarily need to pass antigens through MHC molecules to identify and kill target cells;
NK cell therapy is becoming a very promising field of clinical research, but there are still many challenges to be solved, such as immunosuppression in TME, NK cell proliferation and lack of growth factors necessary for survival.
future treatments must not only target NK cells at tumor cells, but also maximize the effectiveness of therapeutic NK cell products by increasing the persistence of these lymphocytes in the body.
: Myers, J. A., Miller, J. S. Exploring the NK cell platform for immuno cancertherapy. Nature Reviews Clinical Oncology (2020)