Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation

Lactic acidosis is common to most solid tumors and has been found to affect infiltrating immune cells. Here we document effector phase inhibition of cytotoxic T cells (CTLs) involving complete blockage of cytokine production and partial impairment of lytic granule exocytosis. Lactic acidosis impaire...

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Bibliographic Details
Published in:International journal of cancer 2012-08, Vol.131 (3), p.633-640
Main Authors: Mendler, Anna N., Hu, Bin, Prinz, Petra U., Kreutz, Marina, Gottfried, Eva, Noessner, Elfriede
Format: Article
Language:English
Subjects:
Acidosis
Acidosis, Lactic - metabolism
adoptive T cell therapy
Biological and medical sciences
Cancer
Cancer therapies
Cell activation
Cell Line, Tumor
Cell therapy
Cytokines
cytotoxic T cells
Cytotoxicity
Cytotoxicity, Immunologic
Effector cells
effector phase inhibition
Exocytosis
Humans
Hydrogen-Ion Concentration
Interferon-gamma - biosynthesis
JNK Mitogen-Activated Protein Kinases - metabolism
lactic acid
Lactic Acid - metabolism
Lactic acidosis
Lymphocytes T
MAP Kinase Signaling System
Medical research
Medical sciences
Mutation
Neoplasms - immunology
Neoplasms - metabolism
p38 Mitogen-Activated Protein Kinases - metabolism
Phosphorylation
Receptors, Antigen, T-Cell - physiology
Recovery of function
Solid tumors
T cell receptor signaling
T cell receptors
T-Lymphocytes, Cytotoxic - immunology
T-Lymphocytes, Cytotoxic - metabolism
Tumor-infiltrating lymphocytes
Tumors
γ-Interferon
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Summary:Lactic acidosis is common to most solid tumors and has been found to affect infiltrating immune cells. Here we document effector phase inhibition of cytotoxic T cells (CTLs) involving complete blockage of cytokine production and partial impairment of lytic granule exocytosis. Lactic acidosis impaired TCR‐triggered phosphorylation of JNK, c‐Jun and p38, while not affecting MEK1 and ERK. The select targeting of signaling proteins involved in IFNγ production (JNK/c‐Jun, p38) without affecting those jointly used in cytokine regulation and granule exocytosis (MEK1/ERK) explains the observed split effect of lactic acidosis on the CTL responses. CTL inhibition by lactic acidosis showed fast dynamics with immediate onset and reversion. Functional recovery by neutralizing the extracellular pH despite continuous presence of lactate holds promise that CTL activity can be improved in the milieu of solid tumors with appropriate anti‐acidosis treatment, thereby increasing the efficacy of adoptive T cell therapy.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.26410