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    Home > Active Ingredient News > Antitumor Therapy > EMBO Mol Med: Revealing why the use of DR5 agonist antibodies to treat solid tumors such as triple-negative breast cancer and ovarian cancer has repeatedly failed

    EMBO Mol Med: Revealing why the use of DR5 agonist antibodies to treat solid tumors such as triple-negative breast cancer and ovarian cancer has repeatedly failed

    • Last Update: 2021-04-23
    • Source: Internet
    • Author: User
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    News from April 20, 2021/bioon.
    com" target="_blank">/---The lack of effective immune cell infiltration is an important obstacle to the immunotherapy of solid tumors.
    Activating the death receptor-5 (DR5) antibody enriched in solid tumors to achieve tumor cell reduction through external apoptotic cytotoxicity is still an important alternative treatment strategy and a promising treatment for solid tumors Strategy.
    In the past few decades, many DR5 agonist antibodies entered clinical trials after successfully controlling tumors in immunodeficiency tumor xenografts.
    However, all clinically tested DR5 agonist antibodies proved to be unsuccessful in phase II
    bioon.
    com/course_video/lin-chuang-shi-yan-de-feng-xian-jian-kong239833.
    html">clinical trials of solid tumors and failed to significantly improve survival rates.
    This has prompted efforts to develop second-generation DR5 agonists in order to achieve super large-scale apoptotic cytotoxicity in tumors.
    As the control of the immune system has become a powerful tool for tumor treatment, before realizing the true clinical potential of DR5 agonist antibodies, there is still a major question: whether there is an undiscovered immune evasion mechanism that offsets the anti-
    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">tumor activity and may lead to DR5 What about the clinical failure of agonist antibodies?

    bioon.
    com" target="_blank">bioon.
    com/course_video/lin-chuang-shi-yan-de-feng-xian-jian-kong239833.
    html">Clinical trial bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">tumor

    In view of the elevated levels of PD-L1 carried by triple-negative bioon.
    com/tags/%E4%B9%B3%E8%85%BA%E7%99%8C/">breast cancer (TNBC), ovarian cancer and other solid tumors, and considering the lack of immune activation function in the combination therapy of albumin-bound paclitaxel (nab-paclitaxel) and DR5 agonist, from In a new study, researchers from research institutions such as the University of Virginia in the United States tested a view that PD-L1-mediated immune evasion could potentially lead to lower anti-tumor responses of DR5 agonist antibodies.
    To this end, they used a variety of clinical DR5 agonist antibodies, a variety of solid tumor cell lines, and animal
    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">tumor models with sufficient immunity .
    Related research results were recently published in the journal EMBO Molecular Medicine, with the title of the paper "Unexpected PD-L1 immune evasion mechanism in TNBC, ovarian, and other solid tumors by DR5 agonist antibodies".

    bioon.
    com/tags/%E4%B9%B3%E8%85%BA%E7%99%8C/">Breast cancer bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">tumors

    png" target="_blank">

    png" target="_blank">

    These authors found that in the solid tumor cell lines tested, a variety of clinical DR5 agonist antibodies stabilized PD-L1 in tumor cell lysates.
    Blocking the death-inducing signal complex (DISC) containing caspase-8 can inhibit the stabilization of PD-L1.
    Compared with animals treated with control IgG1,
    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">tumor cells from animals treated with DR5 agonist antibody have higher total PD-L1 expression and cell surface PD-L1 expression.

    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">Tumor

    Given the inverse relationship between bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">tumor metastasis and patient survival, these authors next tested whether the stability of PD-L1 mediated by the DR5 antibody would be lost during transient epithelial-mesenchymal transition (EMT).
    To this end, they used the lung cancer cell line A549 to induce transient EMT, and found that DR5 expression, sensitivity to DR5 agonists, and PD-L1 surface stabilization remained unaffected in these metastatic transformed cells.
    Next, through continuous exposure to increasing concentrations of lexatumumab (a DR5 agonist antibody) for 3 months, they developed DR5-resistant ovarian cancer cell lines and TNBC cancer cell lines.
    PD-L1 stabilization was not observed in ovarian cancer cell lines and TNBC cancer cell lines resistant to DR5 signaling.

    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">Tumor

    In tumor cells treated with DR5 agonist antibodies in vitro, inhibiting a variety of protein molecules that regulate the stability of post-translational PD-L1, such as mTOR, STAT3, CDK1 and NF-kβ, does not change the surface expression of PD-L1.
    In addition, compared with untreated tumor cells, transcription inhibitors (actinomycin D) and translation inhibitors (cycloheximide) cannot reverse the stability of PD-L1 induced by DR5 agonist antibodies.
    However, inhibiting DISC-caspase-8 activity will reduce the PD-L1 activity of these
    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">tumor cells.

    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">Tumor

    Given that the DR5 ligand Apo2L belongs to the TNF superfamily, and TNF-α has recently been found to stabilize PD-L1 by activating the deubiquitinating enzyme CSN5 (COP9 signalosome 5), these authors tested DR5-mediated PD-L1 stabilization Whether CSN5 is also required for chemistry.
    TNBC tumor cells were treated with DR5 agonist antibody and TNF-α, respectively.
    TNF-α can stabilize PD-L1 and CSN5 in TNBC tumor cells, as well as in ovarian cancer cells.
    No up-regulation of CSN5 was detected in tumor cell lysates treated with DR5 agonist antibody.
    They also observed that the combined treatment of TNF-α and the proteasome inhibitor MG132 can increase the basic stability of PD-L1 in tumor cells.
    Significantly, prolonged proteasome inhibition increased the total PD-L1 level in tumor cell lysates, but the combined treatment of DR5 agonist antibody and MG132 did not further increase PD-L1 on the cell surface and total PD -L1 in
    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">tumor cell lysates.
    -The stability of L1.
    These results indicate that proteasome inhibition (via MG132) is potentially a downstream event of the DR5 agonist signaling pathway.

    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">Tumor

    Heterogeneous tumors are composed of DR5 sensitive tumor cells (A), DR5 partially sensitive tumor cells (B), and DR5 potentially resistant tumor cells (C).
    Among sensitive tumor cells, cell death caused by DR5 agonists exceeds the tumor clearance threshold.
    It activates caspase-8 and caspase-3, inactivates proteasome function and stabilizes PD-L1 in cells.
    Activated ROCK1 potentially helps mobilize PD-L1 to the membrane through some unknown mechanism.
    Apoptotic cell-derived extracellular vesicles (ApoEV) derived from apoptotic cells also release PD-L1.
    These ApoEVs containing PD-L1 shuttle and transfer the cargo PD-L1 to other DR5 resistant cells in the tumor to increase the overall basic pool of PD-L1 in the tumor.
    At the same time, due to the cytotoxicity mediated by the external DR5 agonist, tumor cells are eliminated, resulting in partial tumor regression and degradation.
    However, due to the overactivity of PD-L1, immune effector cells including T cells in the infiltrating tumor are depleted, thereby limiting their anti-tumor response.
    Co-targeting ROCK1-DR5 can reduce the ApoEV-stabilized PD-L1 pool in tumors, while anti-PD-L1-DR5 co-targeting can reduce the immunosuppressive function of basic PD-L1 and ApoEV-stabilized PD-L1 in
    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">tumors .

    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">Tumor

    png" target="_blank">
    PD-L1 stabilization has nothing to do with CSN5, but depends on protease.
    Picture from EMBO Molecular Medicine, 2021, doi:10.
    15252/emmm.
    202012716.

    png" target="_blank">

    To this end, these authors used the CRISPR-Cas-9 method to generate DR5 knockout (DR5-KO) TNBC tumor cells.
    The resulting DR5-KO tumor cells were not sensitive to DR5 agonists and did not mobilize PD-L1 on the surface of tumor cells.
    It must be pointed out that, compared with DR5 wild-type tumor cells, TNF-α-mediated PD-L1 stabilization remains unchanged in DR5-KO tumor cells.
    After DR5 agonist treatment, the regulatory subunit S5a/PSMD4 of the proteasome was only degraded in DR5 wild-type tumor cells, but not in DR5-KO tumor cells (or DR5 resistant tumor cells).
    In addition, TNF-α signal stabilizes PD-L1 without affecting S5a levels.
    Considering that DR5 agonist degradation of S5a represents an interference with proteasome function, after treatment with DR5 agonist antibody Lexa or KMTR2, the overall ubiquitin signal only increases in DR5-sensitive tumor cell lysates, while in DR5-KO tumor cells There is no increase in it.
    In summary, these results confirmed two different proteasome interference mechanisms for PD-L1 stabilization, one of which works by deubiquitinating PD-L1, and the other by degrading the proteasome subunits.
    kick in.
    Further experiments have shown that ROCK1, located downstream of the DR5 agonist signaling pathway , plays an important role in helping to mobilize the internally stabilized PD-L1 on the surface of
    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">tumor cells (perhaps through CMTM6 or other unknown mechanisms).

    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">Tumor

    In order to study human DR5 agonists for clinical testing under heterogeneous mixed tumor transplantation conditions in vivo, these authors combined the human DR5 extracellular domain (ECD) with the mouse DR5 transmembrane domain (TM) and intracellular structure Domains (ICD) are merged together.
    The DR5 construct thus formed was expressed in mouse 4T1, MC38 and ID8 tumor cells by lentivirus infection, and the cells expressing the DR5 construct were transplanted into mice.
    By carrying out mouse survival studies, they found that co-targeting DR5-PD-L1, DR5-ROCK1, or DR5-PD-L1-ROCK1 significantly increased their survival compared to only targeting DR5 or PD-L1.
    Further experiments showed that this functional targeting resulted in a significant enrichment of CD8+CD45+T cells and CD4+CD45+T cells in the tumor.
    Compared with only receiving DR5 agonist antibody treatment, receiving DR5 agonist antibody and PD-L1 inhibitor treatment at the same time allows tumors to have a higher CD8+/CD4+ ratio and higher granzyme B activity (cytotoxic T cell function) A sign).
    At the same time, the two combined treatments did not increase the activity of regulatory T cells in the tumor.
    This indicates that this combined treatment can increase the anti-tumor immune function and
    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">tumor- killing ability of DR5 agonist antibodies .

    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">Tumor

    Next, these authors genetically modified the PD-L1 inhibitor avelumab and the mouse DR5 agonist antibody MD5-1 into a bispecific antibody called avelu-MD5-1.
    This bispecific antibody not only Blocks the immunosuppressive function of PD-L1 and can also enhance DR5-DISC clustering.
    When tested in a TNBC homologous tumor model, avelu-MD5-1 caused complete tumor regression.
    In contrast, using only similar doses of avelumab or MD5-1 could only
    stabilize the
    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">tumor .

    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">Tumor

    In summary, these authors discovered the unexpected discovery that DR5 agonist antibodies activate PD-L1.
    They also found that caspase-8 and ROCK1 signaling pathways activated by DR5 agonist antibodies regulate PD-L1 stabilization and tumor cell surface mobilization.
    In addition, ApoEV helps to transfer the stabilized PD-L1 pool from DR5-sensitive tumor cells to DR5-resistant tumor cells in mixed heterogeneous tumors, thereby strengthening the immunosuppressive tumor microenvironment.
    The combined targeting of DR5-ROCK1 or DR5-PD-L1 can improve the anti-
    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">tumor function of DR5 agonist antibodies .
    (Bioon.
    com)

    bioon.
    com/course_video/chang-fei-bian-ma-RNA-yu-zhong-liu959063.
    html">Tumor

    References:

    Tanmoy Mondal et al.
    Unexpected PD-L1 immune evasion mechanism in TNBC, ovarian, and other solid tumors by DR5 agonist antibodies .
    EMBO Molecular Medicine, 2021, doi:10.
    15252/emmm.
    202012716.

    Reference materials:

    Tanmoy Mondal et al.
    Unexpected PD-L1 immune evasion mechanism in TNBC, ovarian, and other solid tumors by DR5 agonist antibodies .
    EMBO Molecular Medicine, 2021, doi:10.
    15252/emmm.
    202012716.
    Unexpected PD-L1 immune evasion mechanism in TNBC, ovarian, and other solid tumors by DR5 agonist antibodies
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