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

• 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
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.26410

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.