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    Home > Active Ingredient News > Antitumor Therapy > TIPE2: A new immune checkpoint molecule for NK cells

    TIPE2: A new immune checkpoint molecule for NK cells

    • Last Update: 2021-11-13
    • Source: Internet
    • Author: User
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    ← Skip left and right to view, click [Read the original text] to learn more → The immunosuppressive signal in the tumor microenvironment, through the inhibitory receptor on the T cell, inhibits the anti-tumor T cell response, which is the traditional CAR-T solid tumor curative effect One of the bad factors
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    The use of "inhibitory-to-stimulatory" (Inhibitory-to-stimulatory, ITS) chimeric receptors and the use of inhibitory receptor cell tumor necrosis factor-α inducible protein 8-like 2 (TIPE2) in the extracellular segment is a new discovery of natural immunity and The negative regulator of acquired immunity plays an important role in maintaining immune homeostasis
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    Studies have found that mice lacking TIPE2 are resistant to tumor growth, indicating that TIPE2 may inhibit the anti-tumor immune response
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    TIPE2 can also promote the differentiation of immunosuppressive M2 macrophages and is necessary for CD4+CD25+Treg immunosuppressive function
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    TIPE2 has an effect on the differentiation and function of immunosuppressive leukocytes, but the role of TIPE2 in NK cells has not been revealed
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    Recently, a study on "TIPE2 is a checkpoint of natural killer cell maturation and antitumor immunity" was published in a sub-Journal of Science and found that TIPE2 is a potential checkpoint molecule for NK cell maturation and antitumor immunity
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    Targeting TIPE2 may become a new immunotherapy method based on NK cells
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    The study first investigated the expression patterns of TIPE2 in different stages of NK cells, and found that the expression of TIPE2 in mouse NK cells increased with the individual development of mice and the maturation of NK cells, which also occurred in different expression stages of human NK cells.
    In the same trend, these results reveal that TIPE2 plays an important role in the maturation of NK cells
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    In order to explore the role of TIPE2 in the maturation of NK cells, the study analyzed the level and phenotype of NK cells in NK-specific TIPE2-deficient mice and WT mice
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    Studies have found that NK-specific TIPE2 deficiency can lead to an increase in the number of NK cells
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    In NK-specific TIPE2-deficient mice, the percentage of CD11b+CD27− terminally mature NK cells in the total NK cells and the absolute numbers in the spleen and bone marrow were significantly higher
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    These results indicate that the lack of NK-specific TIPE2 does promote the maturation of NK cells, and TIPE2 can essentially inhibit the maturation of NK cells
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    NK cells often obtain the best effector function during maturation
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    Then we further explored whether TIPE2 deficiency can promote the effector function of NK cells
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    The in vivo killing test of MHC-I low RMAS cells sensitive to NK showed that NK-specific TIPE2-deficient mice cleared significantly more RMAS cells
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    Consistent with this, TIPE2-deficient NK cells also showed stronger killing activity to YAC-1 cells sensitive to NK in vitro, and MC38 cells that were insensitive to NK after stimulation with IL-12, IL-15 and IL-18 Shows stronger killing activity
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    The above data all indicate that the lack of NK-specific TIPE2 promotes the function of NK cell effectors
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    In order to explore the possible mechanism of TIPE2-mediated inhibition of NK cell maturation and effector function, the study investigated whether TIPE2 can regulate the response of NK cells to IL-15, because IL-15 is a cell that plays a key role in NK cell maturation and effector function.
    Factor
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    The study found that after 3 days of IL-15 stimulation, the NK-specific TIPE2-deficient group had significantly more NK cells than the control group
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    IL-15 significantly enhanced the up-regulation of CD69 and the nutrient receptor CD71, which are the activation markers of TIPE2-deficient NK cells
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    These data indicate that the lack of NK-specific TIPE2 promotes the response of NK cells to IL-15, suggesting that TIPE2 may inhibit IL-15 signal transduction in NK cells
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    During the development of NK cells, the activation of mTOR kinase is critical to the transmission of IL-15 signals
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    Studies in vivo and in vitro have proved that TIPE2 inhibits IL-15-mediated mTOR activity, thereby inhibiting the maturation of NK cells
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       The final study investigated whether NK-specific TIPE2 deficiency also affects tumor surveillance in vivo
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    Through investigation, it is found that NK-specific TIPE2 mice are indeed more resistant to tumor growth in vivo than Tipe2WT mice, which is evidenced by the significant reduction in the growth of MC38, RMAS and LLC tumors
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    Therefore, the lack of NK-specific TIPE2 can enhance the anti-tumor function of NK cells
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    The editor concludes that NK cells must undergo a maturation process to reach the optimal functional state of host immune surveillance, and the maturation process must be strictly regulated
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    However, the negative mechanisms that limit the maturation of NK cells are still poorly understood
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    In this study, the investigation found that TIPE2 protein has an expression pattern related to NK cell maturation, and acts as a negative regulator to inhibit NK cell maturation, and enhance the effector function through mTOR activity triggered by IL-15
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    NK-specific TIPE2-deficient mice are more resistant to tumor growth
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    These results suggest that TIPE2 is a checkpoint for NK cell maturation and anti-tumor immunity.
    Targeting TIPE2 is beneficial to NK-based tumor immunotherapy
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