• Breaking the shield that protects pancre

    From ScienceDaily@1:317/3 to All on Thursday, May 05, 2022 22:30:40
    Breaking the shield that protects pancreatic cancer from immunotherapy


    Date:
    May 5, 2022
    Source:
    UT Southwestern Medical Center
    Summary:
    Scar-like cells that make up a sizable portion of malignant
    pancreatic tumors and shield these cancers from immune attack are
    derived from mesothelial cells that line tissues and organs, a new
    study suggests. The findings could offer a new strategy to fight
    pancreatic cancer, a deadly disease for which no truly effective
    treatments exist.



    FULL STORY ========================================================================== Scar-like cells that make up a sizable portion of malignant pancreatic
    tumors and shield these cancers from immune attack are derived from
    mesothelial cells that line tissues and organs, a new study led by UT Southwestern researchers suggests. The findings, published in Cancer
    Cell, could offer a new strategy to fight pancreatic cancer, a deadly
    disease for which no truly effective treatments exist.


    ==========================================================================
    "By targeting antigen-presenting cancer-associated fibroblasts, we might someday be able significantly to enhance the activity of immune therapy in pancreatic cancer patients," said Huocong Huang, M.D., Ph.D., Instructor
    of Surgery at UTSW. Dr. Huang co-led the study with Rolf A. Brekken,
    Ph.D., Professor of Surgery, Pharmacology, and in UTSW's Hamon Center
    for Therapeutic Oncology Research, and a member of the Harold C. Simmons Comprehensive Cancer Center.

    According to the American Cancer Society, about 56,000 people in the
    U.S. are diagnosed each year with pancreatic ductal adenocarcinoma (PDA),
    the most common form of pancreatic cancer. Currently the fourth-leading
    cause of cancer- related deaths in this country, it's projected to
    become the second-leading cause by 2030. Despite decades of research,
    the prognosis for PDA remains dismal, with only 10% of patients surviving
    five years past diagnosis.

    Researchers have long known that cells called cancer-associated
    fibroblasts (CAFs) make up a significant portion of pancreatic
    tumors. Much like the fibroblasts that compose scar tissue, CAFs make pancreatic tumors dense and tough, preventing chemotherapies and other treatments from readily reaching cancer cells. Although scientists had considered these pancreatic CAFs to be a uniform population, Dr. Huang explained, he and his colleagues in the Brekken lab showed in an earlier
    study in 2019 that these cells fall into three categories. One of these
    is a subtype known as antigen-presenting CAFs (apCAFs), which interact
    with immune cells by displaying proteins called antigens on their surface.

    To determine how apCAFs contribute to PDA progression, Dr. Huang,
    Dr. Brekken, and their colleagues used a technique known as lineage
    tracing to learn how these cells arise as a normal pancreas develops
    cancer. Their findings showed that apCAFs originate from mesothelial
    cells, which form a protective membrane that lines organs, body cavities,
    and tissues.

    Further experiments showed that the antigens on the surface of apCAFs
    could convert immune cells called T-cells into a subset known as
    regulatory T-cells (Tregs), which shield tumors from immune attack. When
    the researchers dosed mice carrying pancreatic tumors with antibodies
    against mesothelin, a protein unique to mesothelial cells, the conversion
    to Tregs was blocked, leaving tumors more vulnerable to an anti-tumor
    immune response.

    Although more research is necessary in animal models, Dr. Huang noted
    that it may eventually be possible to employ a similar strategy to treat
    PDA in humans by administering anti-mesothelin antibodies in combination
    with immunotherapies that stimulate the immune system to fight cancers.

    Dr. Brekken, an Effie Marie Cain Research Scholar, noted that the study clarifies the origin and function of apCAFs in PDA but has implications
    beyond pancreatic cancer, an area that Dr. Huang will continue to
    investigate.

    Other UTSW researchers who contributed to this study include Yuqing Zhang, Debolina Ganguly, Raghav Chandra, Gilbert Murimwa, Steven Wright, Xiaowu
    Gu, and Ravikanth Maddipati.

    This study was funded by the National Institutes of Health (K99 CA252009,
    R01 CA243577 and U54 CA210181 Project 2), the Effie Marie Cain Fellowship,
    and the Jean Shelby Fund for Cancer Research at the Communities Foundation
    of Texas.


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


    ========================================================================== Journal Reference:
    1. Huocong Huang, Zhaoning Wang, Yuqing Zhang, Rachana N. Pradhan,
    Debolina
    Ganguly, Raghav Chandra, Gilbert Murimwa, Steven Wright, Xiaowu
    Gu, Ravikanth Maddipati, So"ren Mu"ller, Shannon J. Turley, Rolf
    A. Brekken.

    Mesothelial cell-derived antigen-presenting cancer-associated
    fibroblasts induce expansion of regulatory T cells in pancreatic
    cancer. Cancer Cell, 2022; DOI: 10.1016/j.ccell.2022.04.011 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/05/220505143826.htm

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