Acidity perturbs IL-2 responsiveness, mTORC1 and c-Myc in CD8+ T cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1123221 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29377800.fastq.gz | Fastqsanger.gz | |||
| SRR29377801.fastq.gz | Fastqsanger.gz | |||
| SRR29377802.fastq.gz | Fastqsanger.gz | |||
| SRR29377803.fastq.gz | Fastqsanger.gz | |||
| SRR29377804.fastq.gz | Fastqsanger.gz |
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Project description:CD8+ T cells have critical roles in tumor control, but a range of factors in their microenvironment such as low pH can suppress their function. Here, we demonstrate that acidity restricts T-cell expansion mainly through impairing IL-2 responsiveness, lowers cytokine secretion upon re-activation, and reduces the cytolytic capacity of CD8+ T cells expressing low-affinity TCR. We further find decreased mTORC1 signaling activity and c-Myc levels at low pH. Mechanistically, nuclear/cytoplasmic acidification is linked to mTORC1 suppression in a Rheb-, Akt/TSC2/PRAS40-, GATOR1- and Lkb1/AMPK-independent manner, while c-Myc levels drop due to both decreased transcription and higher levels of proteasome-mediated degradation. In addition, lower intracellular levels of glutamine, glutamate, and aspartate, as well as elevated proline levels are observed with no apparent impact on mTORC1 signaling or c-Myc levels. Overall, we suggest that, due to the broad impact of acidity on CD8+ T cells, multiple interventions will be required to restore T-cell function unless intracellular pH is effectively controlled.
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Project description:Since gastric cancer (GC) is characterized by amplifications of receptor tyrosine kinases (RTK) and KRAS, targeting the RTK/KRAS downstream pathways could contribute to broader applicability of molecular targeted therapy in GC. Here, we assembled a panel of 49 GC cell lines and screened predictors for responsiveness to RAF/MEK/ERK pathway inhibition by comparing their sensitivity to MEK inhibition with alteration status of RTK/KRAS and phosphorylation status of RTK/KRAS downstream molecules. We found that GC cells with MET amplification or KRAS mutation tend to be sensitive to MEK inhibition. Furthermore, lower phosphorylation levels of mTORC1 targets, p70S6K and 4EBP1, was also significantly associated with sensitivity to MEK inhibition. Interestingly, the sensitive cells showed reduced mTORC1 activity accompanied by decreased rate of protein synthesis after MEK inhibition, suggesting that antiproliferative effect of MEK inhibition may be exerted through inhibition of protein synthesis, which was caused by reduced mTORC1 activity. Mechanistically, expression of some mTORC1 negative regulators, such as DDIT4, FOXO3, SESN1 and TSC1, were induced by MEK inhibition in highly-sensitive cell lines and knockdown of these negative regulators partially alleviated the suppression of mTORC1 activity and antiproliferative effect of MEK inhibition. Our data suggest that a subset of GCs, which would be distinguishable according to the predictive markers we identified, may be sensitive to MEK inhibition and have implications for the strategy in clinical trial of MEK inhibitors for GC.
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