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Killer Artificial Antigen Presenting Cells (KaAPC) for Efficient In Vitro Depletion of Human Antigen-specific T Cells
Published on: August 11, 2014
Acidic pH inhibits non-MHC-restricted killer cell functions
B Fischer1, B Müller, K G Fischer
1Institut für Biophysik und Strahlenbiologie, Albert-Ludwigs-Universität Freiburg, Albertstrasse 23, Freiburg i. Br., D-79104, Germany.
Solid tumors create an acidic environment that impairs immune cell function. This study shows acidic pH inhibits key cytotoxic mechanisms, hindering anti-tumor responses and immunotherapy effectiveness.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Physiology
Background:
- Immunotherapy for advanced solid tumors has limited success.
- Tumor microenvironments often exhibit acidic interstitial pH.
- Acidic pH is implicated in tumor cell immune evasion.
Purpose of the Study:
- Investigate the impact of acidic extracellular pH on immune effector cell functions.
- Elucidate mechanisms by which acidic pH inhibits anti-tumor cytotoxicity.
- Assess the effect of pH on various immune cell killing pathways.
Main Methods:
- Utilized peripheral blood mononuclear cells (PBMC) and IL-2-activated LAK cells as effector cells.
- Assessed cytotoxic activity against TNFalpha-sensitive/resistant and Fas-positive/negative tumor cells.
- Manipulated extracellular pH and calcium levels to analyze killing pathways (perforin/granzymes, TNFalpha, Fas/FasL).
Main Results:
- Declining extracellular pH significantly inhibited perforin/granzyme release, TNFalpha secretion, and Fas/FasL-mediated cytotoxicity.
- Acidic pH also affected the secretion of IFNgamma, IL-10, and TGF-beta(1).
- A pH of 5.8 nearly abolished effector cell function by impairing mitochondrial activity and intracellular pH regulation.
Conclusions:
- Tumor acidity severely compromises essential immune effector cell functions.
- Acidic tumor microenvironments contribute to immunosuppression in vivo.
- Targeting tumor acidity could enhance anti-tumor immunity and immunotherapy efficacy.
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