期刊
INTERNATIONAL JOURNAL OF CANCER
卷 131, 期 3, 页码 633-640出版社
WILEY
DOI: 10.1002/ijc.26410
关键词
effector phase inhibition; lactic acid; T cell receptor signaling; adoptive T cell therapy; cytotoxic T cells
类别
资金
- Deutsche Forschungsgemeinschaft [SFB-TR36, SFB455, DFG KR1418/7-1]
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 IFN? 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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