Journal
FRONTIERS IN MOLECULAR BIOSCIENCES
Volume 8, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fmolb.2021.687305
Keywords
glutamine deprivation; PD-L1; bladder cancer; T cells; MEK/ERK/c-Jun signaling pathway
Categories
Funding
- National Natural Science Foundation of China [82071750, 81772713, 81472411]
- Taishan Scholar Program of Shandong Province [tsqn20161077]
- Major Science and technology innovation project of Shandong Province [2019JZZY021002]
- Key projects of Qingdao Science and Technology Program [18-6-1-64-nsh]
- Research and Development Program of Shandong Province [2018GSF118197]
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This study found that glutamine deprivation can increase PD-L1 expression and activate the EGFR/MEK/ERK/c-Jun signaling pathway, thereby affecting T cell function.
Few studies have reported whether nutrients in the tumor microenvironment can regulate the expression of PD-L1. Since tumor cells are often situated in a low-glutamine environment, we investigated PD-L1 expression under glutamine deprivation in bladder cancer cells. PD-L1 expression and the activation of the EGFR/MEK/ERK/c-Jun signaling pathway under glutamine deprivation were investigated by qPCR, Western blot, and immunofluorescence analyses. C-Jun-mediated transcriptional regulation of the PD-L1 gene was assessed by ChIP. PD-L1 expression and activation of the EGFR/MEK/ERK/c-Jun signaling pathway were assessed in T24 cells, TCCSUP cells and BALB/c mice with or without glutamine supplementation. Additionally, the impact of PD-L1 expression under glutamine deprivation on the function of T cells was investigated by ELISA. The expression of PD-L1 and EGFR/MEK/ERK/c-Jun pathway activation were elevated by glutamine deprivation, and c-Jun was enriched in the enhancer region of PD-L1. The expression of PD-L1 was considerably impaired by inhibiting the EGFR/MEK/ERK/c-Jun pathway and was elevated by activating this signaling pathway. In addition, the elevated PD-L1 expression and MEK/ERK/c-Jun signaling pathway activation were reduced by glutamine supplementation in vitro and in vivo. PD-L1 upregulation by glutamine deprivation in bladder cancer cells could reduce IFN-. production by T cells. The expression of PD-L1 was upregulated under glutamine deprivation through the EGFR/ MEK/ERK/c-Jun pathway to impair T cell function.
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