• Pushing past pancreatic tumors' defenses

    From ScienceDaily@1:317/3 to All on Wed Feb 16 21:30:50 2022
    Pushing past pancreatic tumors' defenses

    Date:
    February 16, 2022
    Source:
    Cold Spring Harbor Laboratory
    Summary:
    Researchers found that some cancer cells weave a deactivating
    signal into a protective coat of armor, immobilizing and excluding
    T cells that would otherwise kill them. This immune deactivation
    pathway offers a promising new therapeutic approach for pancreatic,
    breast, and colorectal cancers.



    FULL STORY ==========================================================================
    Our immune systems have the potential to find and destroy cancer
    cells. But cancer cells can be clever and develop tricks to evade the
    immune system. Cold Spring Harbor Laboratory Professor Douglas Fearon and
    his former postdoc ZhiKai Wang found one such trick. Cancer cells weave
    a deactivating signal into a protective coat of armor that excludes T
    cells that would otherwise kill them.

    This immune deactivation pathway offers a promising new therapeutic
    approach for pancreatic, breast, and colorectal cancers.


    ==========================================================================
    T cells patrol the body looking for cancers and pathogens. If they and/or
    their immune system teammates find an intruder, the T cells are mobilized
    to attack.

    Wang, currently a research fellow at the University of Science and
    Technology of China in Hefei, discovered this mobilization was disabled
    by a combination of three proteins woven into a protective coating
    surrounding cancer cells: a signal that usually attracts T cells called
    CXCL12, a filament called KRT19, and a protein that fuses the former
    proteins together called TGM2.

    The scientists used genetic editing to turn off the production of KRT19
    or TGM2 in mouse pancreatic tumors. Without KRT19 or TGM2, the cancer
    cells lost the CXCL12-KRT19 protection and T cells were able to infiltrate
    and attack. The pancreatic tumors shrank or disappeared.

    Why did this coat of proteins repel T cells from the tumors? Wang says,
    "It is kind of counterintuitive because CXCL12 is a chemokine (chemical attractant) that attracts immune cells. But we found that CXCL12 is
    in an unusually high concentration on the surface of the cancer cells,
    where it does the opposite by making T cells immobile." CXCL12 usually
    does its work as a single protein. But at high concentrations on the
    surface of cancer cells, the protein is in a complex with KRT19 and
    forms a branch-like network. T cell movement was reduced dramatically
    by this network.

    The study was published in the Proceedings of the National Academies
    of Sciences. In a previous small clinical study of pancreatic cancer
    patients, Fearon and collaborators showed that the drug plerixafor
    (a CXCL12 receptor blocker) increased the infiltration of T cells into patients' pancreatic tumor tissues. The current study now shows why this immunotherapeutic effect occurs.

    Fearon and Wang hope CXCL12 and KRT19 will provide new therapeutic targets
    that boost the immune system's chances of killing off cancer cells.

    ========================================================================== Story Source: Materials provided by
    Cold_Spring_Harbor_Laboratory. Original written by Luis Sandoval. Note:
    Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Zhikai Wang, Philip Moresco, Ran Yan, Jiayun Li, Ya Gao, Daniele
    Biasci,
    Min Yao, Jordan Pearson, Jaclyn F. Hechtman, Tobias Janowitz,
    Raza M.

    Zaidi, Matthew J. Weiss, Douglas T. Fearon. Carcinomas assemble
    a filamentous CXCL12-keratin-19 coating that suppresses T
    cell-mediated immune attack. Proceedings of the National Academy
    of Sciences, 2022; 119 (4): e2119463119 DOI: 10.1073/pnas.2119463119 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/02/220216083000.htm

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