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    Home > Active Ingredient News > Antitumor Therapy > Adaptive immune resistance to AIR at tumor sites: mechanisms and future prospects

    Adaptive immune resistance to AIR at tumor sites: mechanisms and future prospects

    • Last Update: 2022-09-15
    • Source: Internet
    • Author: User
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    Author: Reed Editor: Maruko


    Adaptive immune resistance (AIR) at the tumor site refers to the tumor's immune escape through various strategies to adapt and eventually escape the body's immune system attack, such as interferon γ selectively induced programmed cell death ligand 1 (PD-L1) in tumor cells


    AIR Introduction



    The AIR hypothesis



    AIR classification






    Combination therapy is currently used





    Future combination therapy regimens


    Although the understanding of the mechanism of AIR in various TIME human cancers is still in its infancy, studies have shown that TME is the main place where AIR occurs, and further exploration of treatment options can be divided into three categories: First, changing TME (tumor microenvironment); Second, block the general immunosuppressive mechanism; Third, enhance T cell-mediated immunity
    .

    1 Change TME


    Pattern recognition receptors (PRR) on innate immune cells, including phagocytes and antigen-delivering cells (APCs), detect a variety of molecular entities
    from infectious sources.

    The detection of LIgands by PRRs leads to activation of various signaling pathways and the maturation of APCs, which can activate and elicit antigen-specific T cells
    .

    APC
    can be activated by giving patients a type I interferon, Toll-like receptor (TLR) ligand, or interferon gene stimulator (STING) agonist.

    The results of a phase Ib trial of advanced melanoma showed marginal beneficial effects
    when combined with anti-PD therapy.
    • Localized radiation

    Radiation can have an effect on tissues and cells, triggering innate immunity and subsequently promoting immune infiltration into tumors in some cases, in addition to destroying
    cells.

    Radiation can also induce PD-L1 expression in tumors, and when radiation therapy is combined with anti-PD therapy, a synergistic antitumor effect
    is observed in mouse models.

    However, it should not be considered or used with caution in time type II and type III tumors, as radiation may damage TIL
    .
    • Topical administration of oncolytic viruses

    The use of oncolytic viruses to treat cancer is based on the fact that some viruses replicate only in cancer cells, not in normal cells
    .

    In addition to the inherent tumorolytic properties of viruses, cytokines, recombinant antibodies, T cell binding ligands, and tumor antigens are also modified to modulate the immune response
    .

    2 Block immunosuppression


    Many immunosuppressed control autoreactive immune responses and hyperreactive inflammatory responses
    in the body.

    In contrast to THE AIR mechanism, which is not necessarily induced or promoted by cancer, or even by inflammation, is necessary for the maintenance of normal homeostasis, such as TGFβ family protein-mediated immunosuppression and Treg cell-mediated immunosuppression
    .

    An anti-CCR4 monoclonal antibody, mogamulizumab, depletes circulating Treg cells and is currently being studied in combination with anti-PD therapy for advanced solid tumors (NCT02301130
    ).
    But because these immunosuppressions are often necessary to regulate or control intrinsic autoimmunity or inflammation, blocking these general immunosuppressions may increase adverse effects
    .

    3 EnhanceStrial T cell-mediated immune function


    A major role of anti-PD therapy is to enhance the immune effects already in TME, but it does not produce systemic immunity, so further systemic immunity
    is needed.

    Combining anti-PD therapy with traditional immune-enhancing approaches, including cancer vaccines, cytokine therapy, T-cell adoption therapy, and co-stimulation, can create synergistic effects
    .

     
    • Adoptive T-cell therapy

    For TIME type I and IV tumors, adoptive T-cell therapy, including genetically engineered chimeric antigen receptor (CAR)-T cells and in vitro expanded antigen-specific T cells or TIL, is an effective way to
    increase T cell infiltration in the tumor.

    Metastatic T cells are fully activated and express PD1, and TIL recognition of tumor antigens may lead to IFNγ and other cytokines inducing PD-L1 expression
    in TME.

    Theoretically, time types I and IV can be converted to type II, so combining anti-PD therapy with adoptive T cell therapy is also the trend
    of future immunotherapy.
    • T cell co-stimulation

    Similar to T cell adoption therapy, co-stimulation can greatly facilitate T cell expansion and activation
    .

    TNFRSF9 (also known as 4-1BB or CD137) is a TNFR superfamily co-stimulating receptor expressed on activated CD8+ T cells, NK cells, B cells, and dendritic cells, and the CD137 signal emitted by the agonistic mAb promotes T cell expansion and its effector function, including cytotoxicity and cytokine production, stimulates memory T cell formation and destroys T cell tolerance
    .

    A clinical trial of an anti-CD137 monoclonal antibody as a single agent or in combination with anti-PD therapy for advanced solid tumors has shown good therapeutic efficacy (NCT02179918, NCT02554812
    ).

    6

    conclusion

    Anti-PD therapy has shown that the discovery of tumor-induced AIR mechanisms, as well as selective blockade, has been shown to be effective
    in cancer patients.

    However, as researchers delve into human TME, they have found that in addition to the PD-1/PD-L1 pathway, there may be other AIR mechanisms, and what is known so far is only the tip
    of the iceberg.

    Therefore, further study of other AIR mechanisms that may exist in TME, and designing new treatment options for these mechanisms, will hopefully benefit more cancer patients
    in the future.

    References:

    Kim, T.
    K.
    , Vandsemb, E.
    N.
    , Herbst, R.
    S.
    et al.
    Adaptive immune resistance at the tumour site: mechanisms and therapeutic opportunities.
    Nat Rev Drug Discov 21, 529–540 (2022).
    https://doi.
    org/10.
    1038/s41573-022-00493-5

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