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    Home > Active Ingredient News > Immunology News > Anticancer mechanism of Immunity immune checkpoint protein PD-1 and TIGIT co-blocking therapy

    Anticancer mechanism of Immunity immune checkpoint protein PD-1 and TIGIT co-blocking therapy

    • Last Update: 2022-05-01
    • Source: Internet
    • Author: User
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    Editor-in-Chief | Xi In recent years, immune checkpoint blockade therapy by inhibiting immune checkpoint receptors or their ligands has brought a new dawn to cancer patients
    .

    The 2018 Nobel Prize in Physiology or Medicine was awarded to Tasuku Honjo and James P.
    Allison, scientists who discovered the first immune checkpoint proteins PD-1 and CTLA4
    .

    However, tumor cells usually do not rely on a single escape mechanism to break through the multiple defenses of the human immune system, and a large number of clinical trials have also confirmed that not all patients can benefit from current immune checkpoint blockade therapy
    .

    On the one hand, immune checkpoint proteins play an irreplaceable role in preventing autoimmunity and preventing excessive immune responses
    .

    On the other hand, the compensatory regulation of immune cells by different immune checkpoint proteins such as PD-1, CTLA4, and TIGIT makes the blockade of a single immune checkpoint limited in controlling cancer and reducing mortality
    .

    Therefore, elucidating the regulatory mechanism of different immune checkpoints on immune cells can help to design more targeted cancer immunotherapy in clinical practice
    .

    Immune checkpoint proteins such as PD-1, CTLA4, and TIGIT regulate immune cell activity by inhibiting T cell co-stimulatory signaling pathways such as CD28 and CD226
    .

    Previous studies have shown that PD-1 and CTLA4 attenuate T cell activity mainly by inhibiting the CD28 signaling pathway (Hui et al.
    Science, PMID: 28280247; Kamphorst et al.
    Science, PMID: 28280249; Krummel et al.
    JEM, PMID: 7543139); while TIGIT mainly inhibits T cells by inhibiting the CD226 signaling pathway (Lozano et al.
    PMID: 22427644)
    .

    Clinically, co-blocking of PD-1 and CTLA4 has achieved better cancer therapeutic effects than blockade alone (Rotte, JECCR, PMID: 31196207)
    .

    In addition, early clinical data showed that co-blocking of PD-1 and TIGIT also achieved better efficacy than PD-1 blockade alone (targetedonc.
    com), but the specific mechanism remains to be elucidated
    .

    On March 8, 2022, Ira Mellman/Eugene Y.
    Chiang's team from Genentech and Huinf's team from UC San Diego published in Immunity magazine Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates Research paper on co-blockade to optimize anti-tumor CD8+ T cell responses
    .

    The authors found that the expression of CD226 on CD8+ T cells, the immune cells that kill tumors in the human body, is particularly critical for the efficacy of PD-1 blockade therapy in non-small cell lung cancer
    .

    At the same time, using the BALB/c mouse tumor xenograft model, the authors also found that CD226 knockout mice were significantly less responsive to PD-1 or TIGIT blockade than wild-type mice
    .

    Using CyTOF technology and scRNA seq technology to analyze tumor-infiltrating lymphocytes from patients with non-small cell lung cancer, the authors found that CD226 and CD28 were co-expressed on some CD8+ T cells
    .

    Next, in the study of the signaling mechanism, the authors found that both PD-1 and TIGIT could inhibit the CD226 signaling pathway through the cell line co-culture system and microscopic imaging technology, and their inhibitory effects could be superimposed
    .

    Further studies found that, similar to the molecular mechanism of inhibiting CD28 signaling pathway, PD-1 utilizes its intracellular region to recruit Shp2 phosphatase to inhibit CD226 phosphorylation; while TIGIT competes with CD226 for their common ligand through its extracellular end.
    The way of PVR inhibits CD226, and its intracellular region is not necessary for the inhibition of CD226 signaling pathway
    .

    Therefore, in immune checkpoint blockade therapy, co-blocking of PD-1 and TIGIT can restore the co-activation signal of CD226 to a greater extent than block alone, thereby enabling CD8+ T cells to obtain better immunity active
    .

    The above research results provide a molecular mechanism basis for the co-blocking of PD-1 and TIGIT to achieve better tumor clinical therapeutic effects than PD-1 blockade alone
    .

    Postdoctoral fellow Karl L.
    Banta from Genentech's Ira Mellman team and Xu Xiaozheng from UC San Diego's Huinf team are the co-first authors
    .

    This work was supported by the Genentech Flow Cytometry Division, Animal Experimentation Division, and the Nikon Center for Imaging Microscopy at UC San Diego
    .

    Link to the original text: https:// Publisher: 11th Reprint Notice [Non-original article] The copyright of this article belongs to the author of the article, and you are welcome to forward and share it.
    Reprinting is prohibited without permission.
    The author has all legal rights, and violators will be prosecuted
    .


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