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    Home > Biochemistry News > Biotechnology News > Nature Immunology: Preparing for the long-term exercise of T cells

    Nature Immunology: Preparing for the long-term exercise of T cells

    • Last Update: 2021-07-29
    • Source: Internet
    • Author: User
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    Image: Long-term overactivity of killer T cells called to tumors or infection sites will make them unable to deal with invaders.
    Immunologists call this "depleted" cell state

    .

    Fighting tumors is a marathon, not a sprint
    .
    For anti-cancer T cells, the competition is sometimes too long, and the T cells give up the fight

    .
    Researchers even gave this phenomenon a name: T cell failure

    .

    In a new "Nature Immunology" study, researchers at the La Jolla Institute of Immunology (LJI) report that T cells can be designed to clear tumors without dying due to T cell exhaustion
    .

    LJI professor Dr.
    Patrick Hogan said: "Our idea is to give cells a little armor against the depletion process

    .
    " "These cells can enter the tumor to complete their work, and then they can stay around the tumor as memory cells

    .
    "

    This research is based on decades of collaboration between Hogan and LJI Professor Dr.
    Anjana Rao

    .
    Their work shows the key role of a protein called a transcription factor in the cellular pathway that triggers T cell failure

    .

    This work is important because even with the most advanced cancer immunotherapy, T cell failure will continue to haunt us
    .

    Taking CAR-T therapy as an example, researchers extract T cells from cancer patients and “arm” them by changing the expression of genes that help fight cancer
    .
    Researchers create more of this special T cell and then return them to the patient

    .
    CAR-T therapy is different from immunotherapy, which aims to activate the patient's existing T cell population

    .

    In both methods, T cell exhaustion raises its ugly head
    .
    "Many people have tried to use CAR-T therapy to kill solid tumors, but this is impossible because T cells will be depleted," said Dr.
    Hyungseok Seo, the co-first author of the study, who was formerly in the Rao laboratory.
    Postdoctoral researcher, currently working at Novartis

    .

    This new study solves this problem by giving T cells the ability to fight fatigue itself
    .

    In order to achieve this goal, the researchers screened T cells to discover which transcription factors can promote T cell "effect" programs, which is an important step in preparing T cells to kill cancer cells
    .

    This screening process led the researchers to discover BATF, a transcription factor they discovered that cooperates with another transcription factor called IRF4 to combat the T cell exhaustion program
    .

    In tumor models of mouse melanoma and colorectal cancer, changing CAR-T cells to overexpress BATF can lead to tumor clearance without causing T cell failure
    .
    CAR-T treatment is effective for solid tumors

    .

    "BATF and IRF4 are working together to make T cells better," Seo said
    .

    Further testing showed that although IRF4 is important, it should not be overexpressed like BATF
    .
    In order to achieve maximum effect, BATF is overexpressed in normal cells about 20 times

    .

    Encouragingly, some of the changed T cells also stayed around and became memory T cells
    .
    This is important because T cell failure usually prevents T cells from having a strong memory response to recurrent cancer

    .

    "We not only improved the ability of T cells to fight fatigue-we also improved the ability of cells to fight tumors," said Edahí González-Avalos, co-first author of the study, a graduate student in Rao's lab who led the Bioinformatics analysis of the project
    .

    Hogan believes that overexpression of BATF may be a promising method to improve CAR-T treatment and solve some difficult-to-treat cancer types (such as pancreatic ductal carcinoma)
    .
    These types of cancers are called "immune cold" because they do not trigger a strong anti-cancer response from the immune system

    .
    T cells will not attack them

    .

    Other laboratories have been exploring ways to "warm up" these cold tumors in order to attract T cells
    .
    The LJI team believes that a promising strategy is to combine these methods with targeted transcription factors to make T cells resistant to depletion

    .

    Hogan said: "We don't necessarily need genetically modified methods to do this
    .
    " "If you know the transcription pathway you want, maybe even an oral drug molecule can do this

    .
    "

    The researchers emphasized that BATF is just one of many transcription factors that may play an important role in combating T cell failure
    .

    "We will continue to look for answers," González-Avalos added
    .

    ###

    BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells

     


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