The master of camouflage of tumor cells: the effect of exosomes on the immune surveillance function of NK cells

January 17, 2022 / eMedClub PR News / -- Extracellular vesicles (EVs), including exosomes and microvesicles, due to their ability to exchange components (i.
e.
proteins, lipids and nucleic acids) between cells ), thereby affecting cell behavior, and thus is considered to be an efficient carrier of intercellular communication
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Exosomes are a class of nanovesicles that are formed and released through late endosomal compartments, while microvesicles are released through the plasma membrane, and many studies have been conducted to study the biological activities of various types of vesicles
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Exosomes were first discovered in sheep reticulocytes in 1983, initially exosomes were just excess membrane proteins thought to be released during cell maturation to regulate membrane function
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Exosomes are mainly derived from multivesicular bodies formed by invagination of lysosomal particles in the cell body, and are released into the extracellular matrix after fusion of the outer envelope of the multivesicular body with the cell membrane
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Over the past six or seven decades, research has demonstrated that exosomes play critical roles in human health and biology, including regeneration and cancer metastasis
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In addition, there are some innovative attempts to develop exosomes for diagnostics and as biomolecule delivery agents
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The so-called "misfortune depends on fortune, and fortune lies on misfortune", the role of exosomes on the body has both positive and negative aspects
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Exosomes are like double agents in cells.
They can be used by humans as porters for drug delivery; they can also be countered by tumor cells and become accomplices for tumors to invade the human body
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Recommended reading: "Double-faced agents" exosomes, a spy war in the human body Yi Maimeng reveals the dual role of exosomes in cancer immune surveillance In the past ten years, the academic community has carried out research on tumor exosomes Extensively studied because they carry signals that make tumors aggressive, create tumor microenvironments (TMEs) that can evade immune detection, and promote metastasis
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Growing evidence suggests that cancer-derived EVs have the ability to modulate innate and adaptive immune responses, thereby helping to influence tumor progression
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Natural killer (NK) cells are innate cytotoxic lymphocytes that play a key role in cancer immune surveillance due to their ability to recognize and kill cancer cells
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NKG2D is an activating receptor on NK cells that binds to MIC and ULBP molecules typically induced on injured, transformed or infected cells
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The NKG2D ligand (NKG2DL) can be released in the extracellular milieu via protease-mediated cleavage or extracellular vesicle (EV) secretion, enabling cancer cells to evade NKG2D-mediated immune surveillance
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Recently, a study published in the Journal of Extracellular Vesicle (JEV) detailed the NKG2D ligand MICA*008 with different EVs (ie, small extracellular vesicles [sEVs] and medium-sized extracellular vesicles [mEVs]).
Population-related immunomodulatory properties
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Using a human MICA*008-transfected multiple myeloma (MM) cell line as a model, the researchers found that NKG2D ligands are present in two vesicle populations
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Interestingly, the researchers found that NKG2D is specifically involved in the uptake of vesicles expressing its cognate ligand, providing strong evidence for this that sEVs and mEVs expressing MICA*008 are indeed able to activate NK cells, but not in Prolonged stimulation induces sustained NKG2D downregulation, leading to impaired NKG2D-mediated function
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▲ EV-related MICA*008 induces downregulation of NKG2D (Image source: Reference 1) Notably, the findings suggest that MICA*008 can be transferred to NK cells via vesicles, leading to cannibalism
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By using MM as a model for tumor-NK cell interactions, MICA-expressing EVs were detected in the bone marrow (BM) of a cohort of MM patients, thus suggesting that these vesicles function in the tumor microenvironment by affecting NK cell-mediated functions key role
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▲ MICA*008 was transferred to NK cells by EVs (Image source: Reference 1) NK cells play a key role in cancer immune surveillance due to their ability to recognize and kill cancer cells and to produce a large number of cytokines and chemokines
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NK cell activation relies on a tight balance between activating and inhibitory signals generated by the binding of different receptors
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NKG2D is a C-type lectin-like activating receptor, expressed on NK cells, γδ T cells, CD8+ T cells, and some autoreactive or immunosuppressive CD4+ T cells, and is used to detect and eliminate viral infections and cancer cells Mainly recognize receptors
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➤ How cunning cancer cells escape the 'surveillance' of NK cells In humans, NKG2D binds to MHC class I-associated chain (MIC) A, MICB, and UL16-binding proteins (ULBP1-6), which are normally not expressed or otherwise in normal tissues.
Low expression; however, they are rapidly induced by different types of stress, including tumor transformation, viral and bacterial infections, and autoimmune diseases
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Therefore, the expression of NKG2D ligand (NKG2DL) is often regarded as a "red flag" for immune cell attack
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However, release of NKG2DL in the extracellular milieu via protease-mediated cleavage or EV secretion is a mode of control of its cell surface expression and a mechanism by which cancer cells evade NKG2D-mediated immune surveillance
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In fact, soluble MICA/B levels are often associated with systemic downregulation of NKG2D surface expression, impairing NKG2D-dependent tumor cell lysis
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At the same time, the decreased density of NKG2DL on the tumor cell surface may lead to a decrease in the killing efficiency
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MICA is the most polymorphic of NKG2DL and has attracted much attention due to its impact on MICA biology
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Thus, the truncating mutant allele, MICA*008, commonly found in the Caucasian population, is attached to the plasma membrane via GPI anchoring and is preferentially released in association with exosomes or secreted via exocytosis
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In addition, the presence of other NKG2DLs on EVs has been reported
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Therefore, many studies have shown that NKG2DLs of the MIC and ULBP families are expressed by exosome-like vesicles released by prostate, ovarian cancer cells and melanoma
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NK cells have long been considered critical in the immune surveillance of multiple myeloma (MM), a clonal B-cell malignancy characterized by expansion of bone marrow plasma cells (PCs)
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Notably, many studies have shown that NK cells from patients with advanced MM often exhibit impaired NK cell function and reduced expression of multiple activating receptors
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The activating receptor NKG2D has been reported to play an important role in NK cell-mediated recognition and killing of MM cells, and high levels of soluble MICA in the serum of MM patients are associated with disease progression stages
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In addition, the NKG2D-NKG2DL pathway has been a research hotspot in the targeted therapy of MM
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▲ MICA is associated with BM-derived EVs in MM patients (Image source: Reference 1) In conclusion, accumulation of vesicle-associated NKG2D ligands in the tumor microenvironment may favor NKG2D ligands via NKG2D downregulation or EV-derived NKG2D ligands” Cannibalism of modified NK cells to inhibit NK cell activity
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▲ EVs use MICA*008 to modify NK cells to induce cannibalism (Image source: Reference 1) This study provides new insights into the dual role of NKG2DL in the tumor microenvironment related to EVs; NKG2DL+EV immunostimulatory effect Can be used as a therapeutic strategy aimed at enhancing NK cell activity during chemotherapy by promoting the transient and controlled release of vesicles
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However, the proliferation of vesicle-associated NKG2D ligands and their chronic accumulation can not only suppress NK cell function through NKG2D downregulation, but also lead to decreased NK cell function by promoting NK cell cannibalism, which sheds light on NK inhibition in cancer The new mechanism may promote the research and progress of cancer cell immune escape
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References: 1.
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