February 2, 2023

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How NK cells recognize and kill tumor?

How NK cells recognize and kill tumor?


How NK cells recognize and kill tumor?


Brief Introduction:

Natural killer (NK) cells in peripheral blood is a typical (PB) lymphocytes (5-10%), about 45 years ago, it was first discovered in mice.

Because of the unique chemokine receptors, NK cells distributed differently in healthy tissue. NK cells mainly in the bone marrow, liver, spleen, and PB; however, some of them are also found in lymph nodes.

NK cells were originally described as exert cytolytic activity and directly kill tumor or virally infected cells without any specific immunity, hence the name.


Subsequently, NK cells were found to produce large amounts of cytokines in several physiological and pathological conditions, especially interferon -γ (IFN-γ).

They secrete a variety of pro-inflammatory and immunosuppressive cytokines, including tumor necrosis factor -α (TNF-α); Interleukin -10 (IL-10) and growth factors, such as granulocyte – macrophage colony stimulating factor (GM -CSF), granulocyte colony stimulating factor (G-CSF) and IL-3.


Similarly, several of NK chemokines also produced, for example, CCL2 (MCP-1), CCL3 (MIP1-α), CCL4 (MIP1-β), CCL5 (RANTES), XCL1 (lymphotactin) and CXCL8 (IL-8) cell.

Physiological effects of growth factors produced by NK cells is unclear. NK cells co-localize with other hematopoietic cells (such as dendritic cells (the DC)) in the inflamed area is chemokine induced by them.


In addition, T-cell response in the lymph nodes is controlled by NK cells. NK cells stimulated release of perforin and granzyme to mediate target cell killing (FIG. 1).


How NK cells recognize and kill tumor?


Cell-mediated tumor killing and FIG. 1 NK regulation of the immune system in different ways:

(A) NK cells are capable of presenting antigen to T cells by killing immature DC, while promoting IFN-γ and TNF-α mediated enhancement of DC maturation.

(B) NK cells can specifically recognize their lack of MHC I cells (Missing-self) molecules expression.

(C) ADCC can kill the target cell.

(D) Fas / FasL pathway is a very effective NK cell-mediated killing, as FasL binding to Fas leads pass “death signal” to the target cells, the apoptosis occurs quickly.

(E) factor pathway can exert an antitumor cell potential, as cytokines (e.g., NK cells) secrete a variety of cytokines, such as TNF-α.

(F) NK cell receptor NKG2D recognizes “self-induced” ligands, these ligands in response to activation of tumor-associated passage at a very high speed expression.

(G) checkpoint blocking of NK cells, can be inhibited by preventing the interaction of NK cell inhibitory receptor with its ligand.

(H) Since NK cells adoptively transferred for the mismatch between the donor and acceptor, the inhibitory-KIR, the lack of NK cells eliminate tumor cells allogeneic MHC itself. CAR-NK cells

(I) specific to a tumor antigen overexpressed design may also be used to eliminate certain tumor cells.

(J) designed bispecific molecules are also used to specifically eliminate tumor cells, such as NK cell receptor binding molecules specific activation of one side and the other side of the tumor antigen.

(K) NK cells to enhance or reduce the activity of macrophages and T cells produced by IFN-γ and IL-10 in.


By forming transmembrane perforin (perforation) to increase the permeability of the channel the particles more easily enter the enzyme and causes osmotic lysis on the target cell.

Particles cleavage site and help kill the target cell lysis (FIG. 1). NK cells may indirectly affect DC by secreting IFN-γ.

Interaction naive T cells and NK cells into the secondary lymphoid compartment from the site of inflammation plays an important role in mediating T cell reaction.


As the first line of defense, NK cells prevented from invading pathogens and tumorigenesis.

After infection, NK cells activated quickly, without prior sensitization, in order to avoid infection and abnormal cells.

NK cells in comparison with autologous, allogeneic NK cells generally more effective, more toxic to the tumor.

NK cells were divided into subgroups based on their functional properties and level of maturity. Progress on tumor immunology deep understanding of the biology of NK cells, especially their clinical application in recent years become an interesting research focus areas.


The following describes some unique features make the use of NK cells in the future immunotherapy.



NK receptors and their regulatory mechanisms


Expressed on NK cells of various cell membrane receptors, including activation, inhibition, cytokine and chemokine receptors (FIG. 2).

Present in the canonical and noncanonical major histocompatibility complex (MHC) I molecules is suppressed or NK activating receptors expressed on the cell identified on normal cells.

Balance adjustment and for activation of NK cells between inhibitory and activating receptor signaling use.


How NK cells recognize and kill tumor?


FIG 2 NK cell surface receptor and its corresponding ligand: NK cell activation and inhibition of expression of a large number of cell surface receptors that their respective ligand interactions found in the tumor cell surface.


To identify the corresponding ligand MHC molecule or other inhibitory receptor is down-regulated in tumor cells; however, NK cells are activated and subsequently kill tumor cells (FIG. 1) by so-called “missing self” mechanism.

Typically, present on the cell surface of MHC molecules act as ligands healthy inhibitory receptors, contributes to the establishment of self-tolerance and NK cells.

However, due to the development of tumor cells may lose these molecules, resulting in reduced inhibitory signals to NK cells. Another based receptor – ligand interactions trigger the main mechanism of activation of NK cells is called “self-induced” mechanism.


Several receptor activation, including activation of NKG2D and killer immunoglobulin-like receptors (-KIR), which can identify the corresponding interactive “self-induced” ligands, such ligands are either lacking only on healthy cells, or only expressed on healthy cells, but is highly expressed in cancer cells in response to activation of tumor-related pathways.

Therefore, these “missing self” and “self-induced” change of cell senescence characterized, DNA damage cell stress response and significant forms of tumor suppressor genes, expression of these genes to stimulate a robust activation of receptor ligands.

NK cells were activated in activation of the receptor these effects and cytotoxicity by NK cells mediated by pro-inflammatory cytokines mediated direct or indirect killing of target cell elimination.


Antibody-dependent cellular cytotoxicity mediated by cells (ADCC) is another method of targeting tumor cells.

Characteristics of NK cells is enriched CD16 (FcγRIIIA), CD16 IgG1 and IgG3 as receptor for NK cell mediated ADCC essential.

Activation of the receptor as a prototype NK cells, CD16 can trigger cytotoxicity and cytokine and chemokine secretion, thereby imparting the anti-tumor activity of NK cells.

Some circulating monocytes and macrophages also express CD16, which consists of two extracellular Ig domains, a transmembrane and cytoplasmic tail domains.


Transmembrane domain and help FcεRIγ D16 CD3ζ chain binding, resulting in the formation contains an immunoreceptor tyrosine-based activation motif (the ITAM) subunits, the subunits of these signal transduction pathways in these cells is associated with the subunits to many recombination activating and regulating cytoskeletal elements transcription factors.

In NK cells, the ADCC mediated by such passage, characterized in that the cytotoxic secretory granules (perforin and granzyme) and Fas ligand and targeting TNF-related apoptosis-inducing ligand participation (of TRAIL) death receptor.

Furthermore, CD16 involved in supporting the survival and proliferation of NK cells and stimulate cytokine and chemokine secretion, leading to tumor infiltrating immune cells recruitment and activation.


The main pathway involves NK cell-mediated cytotoxicity of cells known as Fas / FasL pathway. Fas (Apo-1 or CD95) and Fas ligand (FasL or CD95L) are type I and type II transmembrane protein belonging to the TNF family.

When FasL binding to Fas, it sends a “death signal” to the target cells to apoptosis. NK cells secrete various cytokines (e.g. TNF-α) referred cytokine pathways, can kill the target cell / tumor cell.


Macrophages and regulation of T cell responses can kill target cells. NK cells can be enhanced or reduced activity of macrophages and T cells produced by IFN-γ and IL-10.

These cytokines cause the release of lysosomal hydrolases from the target cell by changing the cell membrane phospholipid metabolism.

Such altered metabolic activation of the degradation of the target nucleic acid within the cell genomic DNA endonuclease. NK cells through a crosstalk between DC and NK cell mediated immune response.

NK cells can kill immature DC and promoted by IFN-γ and TNF-α-mediated DC maturation enhance antigen presentation to T cells.


Similarly, another potential mechanism of killing target cells is blocked checkpoint, which prevents the performance of inhibiting the interaction of their respective receptor ligands.

Thus, a mismatch between donor cells and NK cells KIR receptors and MHC class I molecules may start to eliminate target cells.

Furthermore, activation of NK cells CARs on gene expression can specifically bind to a tumor antigen.

Interestingly, bispecific molecules can also be used to simultaneously bind to a tumor antigen on activated receptor and NK cells, to stimulate tumor lysis mediated by NK cells.


Typically, signals for various inhibitory receptors, not activate the receptor, to maintain homeostasis within the host. It acts as a checkpoint inhibitory receptors, such as those T cells to control the activation of NK cells.

PD-1, TIM-3, inhibitory KIR, NKG2A over-expressing the receptor and T-cell immunity in the tumor microenvironment (TME) and viral infections has been reported immunoreceptor tyrosine surface of NK cells inhibitory motif structures domain (TIGIT).


Of DCs and inhibitory receptors, regulatory T cells (of Tregs), the interaction of tumor cells and the respective ligand on the infected cells to generate a signal regulating activation of NK cells, effector function and even subsequent failure.

Thus, NK cell activation can be suppressed by checking the receptor. For example, anti-NKG2A mAb anti-TIGIT and has shown excellent antitumor activity, they can be recovered as anti-tumor activity of NK and T cells.

Recently, cetuximab (anti-EGFR) and Mona natalizumab (anti of NKG2A) a combination of head and neck squamous cell carcinoma objective response rate was 31%.


Identification of HLA class I-specific inhibitory receptors, especially-KIR, reveal potential mechanisms of NK cells to kill tumor cells. The next section provides a quick overview of KIR.



Killer immunoglobulin receptors

KIR-specific expression in human NK cells, encoded by the LRC and is present on human chromosome 19. They may be combined with present on a target cell MHC class I molecules.

They found inhibitory and activating KIR receptor family. Immunoreceptor tyrosine inhibitory KIR used in the extended cytoplasmic tail inhibition motif (an ITIM) to deliver inhibitory signals.

However, with a short tail activating KIR and DAP12 or FcγR use as adapter molecules to activate signal transduction of NK cells.

There are two inhibitory KIR (KIR2DL) or three (KIR3DL) extracellular Ig domains, it has a function specific for HLA molecules.

Thus, as recently as a detailed review, KIR highly sensitive to any changes in cancer and HLA molecules during viral infection.


Usually, KIR is constitutively expressed; however, inhibition signal naturally dominate and inhibit the activation of NK cells and fine-tune the signal in order to protect healthy cells, also known as N cell self-tolerance.

Self-tolerance is believed to be regulated by the binding of some powerful inhibitory receptors (such as KIR and NKG2A) to MHC class I molecules.

Presumably, the expression of MHC class I molecules of cancer (self-deletion) reduced this inhibition can be prevented and the reaction allowed to self.


KIR-HLA mismatches are also important factors to be considered in cancer immunotherapy.

Each KIR a particular HLA allotype recognized as an inhibitory ligand; KIR2DL1, KIR2DL2 / 3 and KIR3DL1, respectively, group 1 HLA-C and HLA-Bw4-specific binding group 2 HLA-C.

Thus, the lack of inhibition of NK cell-specific HLA allotypes receptors may exhibit better and more effective anti-tumor activity.

Several previous studies have reported that, KIR-HLA between donor and recipient mismatch leads to higher anti-tumor potential.


Further, in order to obtain the best anti-tumor effect, consider the actual expression of KIR, since they are typically expressed in the form of random combinations (38).

Interestingly, we did not encounter any single KIR + HLA-suppressed signal allogeneic NK cell-mediated anti-tumor activity.

First, NK cells from hematopoietic stem cell allogeneic transplantation (HSCT) to recover; however, recombinant NK receptor repertoire takes about three months, whereas a single KIR + NK cells before not fully functional.

However, since the MHC mismatch,-KIR mismatched allogeneic NK cells may be rejected.

For example, in a study of KIR / HLA genotype was found in acute kidney caused by KIR / HLA polymorphism transplant rejection.

Similarly, in Phase II clinical trials (NCT00703820) found KIR-HLA mismatched allogeneic NK cells in high-risk acute myeloid leukemia (AML) is invalid, this may be due to insufficient quantity and poor durability.


Trained and licensed NK cells inhibitory receptors, these receptors recognize MHC molecules in response to MHC-I deficient cells.

Expression of inhibitory receptors and to ensure its ability to function in the process of NK cell development. Without these inhibitory receptors of NK cells and permit no access to education and to maintain a low reactivity.

For example, HLA-Bw6 + NK cells in patients with KIR3DL + NK cells react more slowly than KIR3DL HLA-Bw4 patient, because Bw4 as a ligand for KIR3DL1.


Thus, inhibition of the signal may affect the strength of NK cells. In addition, only a small number of autoreactive receptors lacking NK cells are non-reactive, because NK cells in the maturation process of “permission” or “education” gives this feature.

In skin cancer, lymphoma, leukemia, breast cancer and bile duct cancer and other cancers, the inhibitory KIR is reduced, while activating KIR is upregulated.

KIR expression patterns of these variations may help tumor escape by inhibiting NK cell activation and subsequent antitumor activity.


Inhibitory KIR was first considered to be NK cells checkpoint receptor. Since mAb may identify an inhibitory KIR, to enhance their anticancer activity of NK cells by blocking the signal transduction of NK cells.

Thus, compared with other treatment methods, mAb potential therapeutic drug candidates, they are more secure and less side effects, other treatments have been used in clinical trials against a variety of tumor types.


Due to their inhibition of HLA molecules mediate early autologous NK cells disappointing findings.

With the establishment of transplantation KIR ligand mismatched allogeneic NK cells proliferation application in non-hematopoietic stem cell transplantation and hematopoietic stem cell transplantation.

NK cells in comparison with autologous, allogeneic NK cells is not inhibited self-MHC molecules. In addition, a number of studies have shown that injection of haploidentical NK cells into patients with AML Self Missing is safe and can induce a large number of clinical activity.

Found that haploidentical NK cells were adoptively transferred into AML patients was safe, because it does not cause graft-versus-host disease (of GVHD), and administration of IL-2 that their persistence increased about 4 weeks.




doi: 10.3389 / fimmu.2021.707542

How NK cells recognize and kill tumor?

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