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  11. Acidity Induces Durable Enhancement Of Treg Cell Suppressive Functions For Tumor Immune Evasion

Acidity induces durable enhancement of Treg cell suppressive functions for tumor immune evasion

Nikita L Mani1, Samuel E Weinberg1, Shuvam Chaudhuri2

  • 1Department of Pathology, Northwestern University, USA; Center for Human Immunobiology, Northwestern University, USA.

Molecular Immunology
|August 30, 2024

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View abstract on PubMed

Summary
This summary is machine-generated.

Tumor acidity enhances regulatory T (Treg) cell immunosuppression by reprogramming metabolism, but lactate addition reverses this effect. This acidity-induced Treg enhancement promotes tumor growth and immune evasion.

Area of Science:

  • Immunology
  • Cancer Biology
  • Metabolic Regulation

Background:

  • The tumor microenvironment (TME) is often acidic due to metabolic dysregulation, such as increased lactate production.
  • Regulatory T (Treg) cells are crucial for immune evasion in tumors.
  • The specific role of acidity in Treg cell function and adaptation within the TME remains largely unexplored.

Purpose of the Study:

  • To investigate the impact of acidity on Treg cell function and identify underlying molecular mechanisms.
  • To explore the interplay between acidity, lactate, and Treg cell-mediated immunosuppression.
  • To determine if acidity-induced Treg cell enhancement is sustained and impacts anti-tumor immunity.

Main Methods:

  • Treatment of natural Treg (nTreg) and induced Treg (iTreg) cells with acidic conditions and/or lactate.
Keywords:
AcidityFormateLactateOxidative phosphorylation

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  • Analysis of Treg cell surface markers (FoxP3, CD25, CTLA4, GITR) and immunosuppressive function.
  • Metabolic flux analysis, including mitochondrial respiration and glycolysis.
  • Genome-wide transcriptome and metabolomics analyses.
  • In vivo studies using mouse models to assess tumor growth and immune cell infiltration.

    • Main Results:

    • Acidity significantly enhanced the immunosuppressive functions of nTreg cells, but not iTreg cells, without altering key surface markers.
    • Lactate addition abolished the acidity-induced enhancement of nTreg suppressive functions.
    • Acidity increased mitochondrial respiration in nTreg cells and altered one-carbon folate metabolism, reducing SAM, folate, and glutathione levels.
    • Formate, a one-carbon metabolite, diminished acidity-induced Treg enhancement, while SAM and glutathione did not.
    • Transient in vitro acidity treatment led to sustained Treg cell enhancement, promoting tumor growth in vivo and reducing CD8+ T cell frequency and granzyme B production.

    Conclusions:

    • Tumor acidity reprogrammes nTreg cell metabolism, enhancing their immunosuppressive capacity and promoting tumor immune evasion.
    • The one-carbon folate pathway is a key metabolic target of acidity in nTreg cells.
    • Acidity-mediated Treg cell enhancement is sustained and contributes to a suppressive tumor microenvironment, highlighting potential therapeutic targets.
    Suppression
    T(reg) cells