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Mendler, A.N. ; Hu, B. ; Prinz, P.U. ; Kreutz, M.* ; Gottfried, E.* ; Nößner, E.

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

Int. J. Cancer 131, 633-640 (2012)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter effector phase inhibition; lactic acid; T cell receptor signaling; adoptive T cell therapy; cytotoxic T cells; CD8(+) T-CELLS; INFILTRATING LYMPHOCYTES; IMMUNE-RESPONSE; METASTASES; CARCINOMA; CANCERS; PH
ISSN (print) / ISBN 0020-7136
e-ISSN 1097-0215
Zeitschrift International Journal of Cancer
Quellenangaben Band: 131, Heft: 3, Seiten: 633-640 Artikelnummer: , Supplement: ,
Verlag Wiley
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Immunology (IMI)