期刊
CELLULAR SIGNALLING
卷 86, 期 -, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2021.110115
关键词
PKC iota; PDL1; Natural killer cell; Immune evasion; Immunotherapy; Pancreatic cancer
类别
资金
- National Natural Science Foundation of China [81472555]
Inhibition of PKC iota enhances the susceptibility of PDAC to NK cytotoxicity and reduces the immunosuppressive microenvironment by suppressing PDL1 expression. Co-culture with NK92 further induces PDL1 upregulation, leading to immune escape of PDAC cells. Combining PKC iota inhibitor with PD1/PDL1 blocker significantly boosts the cytotoxicity of NK92 against PDAC cells, showing promise for enhancing PDAC immunotherapy.
To investigate the impact of oncogenic protein kinase C isoform iota (PKC iota) on the microenvironment and the immunogenic properties of pancreatic tumors, we prohibit PKC iota activity in various pancreatic ductal adenocarcinoma (PDAC) cell lines and co-culture them with human natural killer NK92 cells. The results demonstrate that PKC iota suppression enhances the susceptibility of PDAC to NK cytotoxicity and promotes the degranulation and cytolytic activity of co-cultured NK92 cells. Mechanistic studies pinpoint that downstream of KRAS, both YAP1 and STAT3 are recruited by oncogenic PKC iota to elevate the expression of PDL1, contributing to constitute an immune suppressive microenvironment in PDAC. Co-culture with NK92 further induces PDL1 upregulation via STAT3 to stimulate immune escape of PDAC cells. Subsequently, inhibition of PKC iota in PDAC alleviates the immune suppression and enhances the cytotoxicity of NK92 towards PDAC through restraining PDL1 over expression. Combined with PD1/PDL1 blocker, PKC iota inhibitor remarkably elevates the cytotoxicity of NK92 against PDAC cells in vitro, establishing PKC iota inhibitor as a promising candidate for boosting the immunotherapy of PDAC.
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