• A potential new target for cancer immuno

    From ScienceDaily@1:317/3 to All on Wednesday, March 16, 2022 22:30:44
    A potential new target for cancer immunotherapies

    Date:
    March 16, 2022
    Source:
    Weill Cornell Medicine
    Summary:
    Tumors can use an enzyme called ART1 to thwart antitumor
    immune cells, making the enzyme a promising new target for
    immunity-boosting cancer treatments, according to a new study.



    FULL STORY ========================================================================== Tumors can use an enzyme called ART1 to thwart antitumor immune cells,
    making the enzyme a promising new target for immunity-boosting cancer treatments, according to a study from researchers at Weill Cornell
    Medicine and Albert Einstein College of Medicine.


    ==========================================================================
    In the study, published Mar 16 in Science Translational Medicine, the researchers found strong evidence that ART1, when expressed on tumor
    cells, can modify a receptor on tumor-fighting immune cells in a way that triggers the death of these immune cells. In animal models of cancer,
    blocking ART1 increased the presence of the tumor-fighting immune cells
    within tumors and slowed or stopped tumor growth.

    "These findings should allow us to add to our medicinal toolkit for
    enhancing the antitumor immune response, to benefit cancer patients,"
    said study co- corresponding author Dr. Timothy McGraw, professor of biochemistry and of biochemistry in cardiothoracic surgery and a member
    of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

    "Our main focus in this study was lung cancer, but there is evidence that
    this immune-evasion mechanism is at work also in other kinds of cancer,"
    said co- corresponding author Dr. Sandra Demaria, professor of radiation oncology and of pathology and laboratory medicine and a member of the
    Meyer Cancer Center at Weill Cornell Medicine.

    "This is an excellent example of how translational science should work. We first found ART1 expressed in the tumors of patients with lung cancer. In
    the lab, we discovered that ART1 helps to block the anti-tumor immune
    response, specifically by inducing death of anti-tumor T cells. We then developed a therapeutic antibody that blocks the function of ART1, allows
    the immune system to fight the cancer and ultimately prolongs survival
    in tumor models," said senior author Dr. Brendon Stiles, formerly of
    Weill Cornell Medicine and now chief of the Division of Thoracic Surgery
    and Surgical Oncology and associate director of surgical services at
    Montefiore Einstein Cancer Center and professor of cardiovascular and
    thoracic surgery at Albert Einstein College of Medicine. "Hopefully, we
    can very soon take that antibody back to treat our patients with cancer."
    The mammalian immune system has various safety mechanisms to prevent
    immune activity from becoming excessive and damaging tissues. Scientists
    in recent decades have come to appreciate that tumors frequently co-opt
    these safety mechanisms -- also called immune checkpoints -- to defeat
    natural antitumor immune responses.

    That appreciation has led, in turn, to the development of "immune
    checkpoint inhibitor" treatments that block these safety mechanisms to
    enhance antitumor immunity. These treatments are now part of standard
    care in several types of cancer and help account for some astounding
    cures. However, a large proportion of individual cancers do not respond
    to such therapies, which hints that these cancers may make use of other, so-far-unrevealed immune checkpoint systems.

    ART1 appears to be part of one such immune-checkpoint exploitation
    system. The researchers found that expression levels of its gene
    were significantly higher in the most common type of non-small-cell
    lung cancer (NSCLC), compared to non- cancerous lung cells. Similarly,
    in mice, ART1-overexpressing NSCLC tumors grew rapidly, while blocking
    ART1 reduced tumor growth. However, this effect on tumors appeared only
    in mice with intact immune systems, implying that blocking ART1 works
    by unleashing antitumor immunity.

    Further experiments in mice with NSCLC and melanoma tumors confirmed that reducing ART1 led to a greater presence within tumors of CD8 T cells,
    the immune system's most powerful weapon against cancers.

    The experiments also provided strong evidence that ART1 interacts with
    a receptor called P2RX7R on CD8 T cells and activates signaling that
    causes the deaths of the CD8 T cells. The P2RX7R receptor therefore
    seems to be an important molecular switch that cancers use to shut down anticancer immunity.

    The researchers then blocked ART1 using a humanized therapeutic antibody
    they had developed -- in a collaboration with the Tri-Institutional Therapeutics Discovery Institute, a partnership including Weill Cornell Medicine, The Rockefeller University, and Memorial Sloan Kettering Cancer Center -- and demonstrated that it slowed tumor growth and prolonged
    survival in mice. Dr.

    Stiles is now further developing the anti-ART1 antibody as a potential
    immune- enhancing cancer treatment.


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


    ========================================================================== Journal Reference:
    1. Erik Wennerberg, Sumit Mukherjee, Sheila Spada, Clarey Hung,
    Christopher
    J. Agrusa, Chuang Chen, Amanda Valeta-Magara, Nils-Petter
    Rudqvist, Samantha J. Van Nest, Mohamed K. Kamel, Abu Nasar,
    Navneet Narula, Vivek Mittal, Geoffrey J. Markowitz, Xi Kathy
    Zhou, Prasad S. Adusumilli, Alain C. Borczuk, Thomas E. White,
    Abdul G. Khan, Paul J. Balderes, Ivo C.

    Lorenz, Nasser Altorki, Sandra Demaria, Timothy E. McGraw,
    Brendon M.

    Stiles. Expression of the mono-ADP-ribosyltransferase ART1 by
    tumor cells mediates immune resistance in non-small cell lung
    cancer. Science Translational Medicine, 2022; 14 (636) DOI:
    10.1126/scitranslmed.abe8195 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/03/220316145725.htm

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