• Scientists identify potential new 'soldi

    From ScienceDaily@1:317/3 to All on Wed Apr 20 22:30:48 2022
    Scientists identify potential new 'soldier' for cancer immunotherapy


    Date:
    April 20, 2022
    Source:
    Memorial Sloan Kettering Cancer Center
    Summary:
    The new cells, which the scientists have dubbed killer innate-like T
    cells, differ in several notable ways from the conventional target
    of many immunotherapies.



    FULL STORY ========================================================================== Despite the success of immunotherapy in helping many people with cancer,
    the majority of patients still do not respond to these treatments. There
    is need for continued research.


    ==========================================================================
    On April 20, 2022, researchers at the Sloan Kettering Institute reported
    in the journal Nature that a recently discovered new immune cell "soldier" could be a good target for immunotherapy, raising hopes that it might
    help narrow the gap between people who respond and those who do not.

    The new cells, which the scientists have dubbed killer innate-like T
    cells, differ in notable ways from the conventional target of many immunotherapies - - the cytotoxic (aka "killer") T cells. For one,
    they don't get exhausted from extended activity like cytotoxic T cells
    do. And two, they can penetrate more deeply into tissues where cancer
    is hiding. These unique attributes make them attractive as a target
    for immunotherapy.

    "We think these killer innate-like T cells could be targeted
    or genetically engineered for cancer therapy," says Ming Li, an
    immunologist in SKI and the lead author of the new study. "They may be
    better at reaching and killing solid tumors than conventional T cells."
    Pinning Down What Makes the Cells Distinct Dr. Li's team first reported
    the existence of this unusual cell population in 2016. At that time, it
    was clear to his team that these cells had the power to kill cancer cells,
    but they knew little about where the cells come from or how they work.



    ==========================================================================
    For this new study, Dr. Li and colleagues used a variety of techniques, including single-cell analysis and CRISPR genome editing, to further characterize the cells.

    They made several startling discoveries. For one, killer innate-like
    T cells don't make the immune checkpoint molecule PD-1 and, as a
    consequence, do not appear to become exhausted the way typical killer
    T cells do. This is an attractive feature in a potential immune cell
    therapy.

    The cells also appear to recognize different markers, or antigens, on
    cancer cells. Whereas conventional killer T cells recognize specific
    mutated antigens (called neoantigens), the killer innate-like T cells
    recognize a much broader range of non-mutated (that is, normal) antigens.

    Killer innate-like T cells also don't depend on antigen-presenting
    cells, such as dendritic cells, to alert them to the presence of dangerous-looking antigens. In this way, they behave more like innate
    immune cells that are always primed and ready for attack.

    Lastly, unlike conventional T cells, they don't recirculate throughout the blood and lymph fluid, making stops in lymph nodes. Rather, they appear to
    home directly to tissues throughout the body, where they seek out danger.



    ==========================================================================
    All of these make them of particular interest as a target of
    immunotherapy, Dr.

    Li says.

    A Unique Fate That Avoids Autoimmunity and Suppresses Cancer The fact
    that killer innate-like T cells recognize unmutated antigens in the
    body raises the question of why these cells don't cause autoimmunity --
    when the immune system attacks normal parts of the body. Dr. Li says
    it's because they get reprogrammed during their development.

    Typically, developing T cells that react strongly to normal antigens are proactively killed off by the body to prevent autoimmune reactions. But
    the killer innate-like T cells escape that fate. Instead, their T cell
    receptor machinery gets tamped down, rendering these cells harmless to
    normal cells in the body.

    At the same time, they become much more sensitive to a molecule
    called IL-15 that is produced by many cancer cells and is recognized
    as an "alarmin" -- a danger signal that prods the immune system into
    action. The team found that if they delete IL-15 from cancer cells, then
    the protection provided by the killer innate-like T cells was eliminated
    and tumor growth increased.

    Because IL-15 isn't highly produced in healthy tissues, the killer
    innate-like T cells would not be spurred into action there, and therefore
    would not cause unwanted damage.

    Dr. Li's team did most of their experiments in mice, but they confirmed
    that these killer innate-like T cells are present in human tumors,
    including colon cancer tumors from patients at MSK. They are excited about
    the possibility of working with doctors at MSK to translate these findings
    from the lab to the clinic, where they might ultimately help patients.

    This work was supported by the National Institute of Health (R01
    CA243904-01A1, F30 AI29273-03, and F31 CA210332), the Howard Hughes
    Medical Institute, the Cancer Research Institute, the Ludwig Center for
    Cancer Immunotherapy and the Functional Genomic Initiative grants, and the Memorial Sloan Kettering Cancer Center (MSKCC) Support Grant/Core Grant
    (P30 CA08748), the Alan and Sandra Gerry Metastasis and Tumor Ecosystems
    Center of MSK.

    MSK has filed a patent application regarding use of killer innate-like
    T cells in cancer immunotherapy. Dr. Li is a scientific advisory board
    member of and holds equity or stock options in, Amberstone Biosciences
    Inc, and META Pharmaceuticals Inc.


    ========================================================================== Story Source: Materials provided by
    Memorial_Sloan_Kettering_Cancer_Center. Note: Content may be edited for
    style and length.


    ========================================================================== Journal Reference:
    1. Chun Chou, Xian Zhang, Chirag Krishna, Briana G. Nixon, Saida Dadi,
    Kristelle J. Capistrano, Emily R. Kansler, Miranda Steele, Jian Han,
    Amy Shyu, Jing Zhang, Efstathios G. Stamatiades, Ming Liu, Shun Li,
    Mytrang H. Do, Chaucie Edwards, Davina S. Kang, Chin-Tung Chen, Iris
    H. Wei, Emmanouil P. Pappou, Martin R. Weiser, J. Garcia-Aguilar,
    J. Joshua Smith, Christina S. Leslie, Ming O. Li. Programme of
    self-reactive innate-like T cell-mediated cancer immunity. Nature,
    2022; DOI: 10.1038/ s41586-022-04632-1 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/04/220420133616.htm

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