Zhang Hongmei, Zhu Yue, Wang Junli, Weng Sijia, Zuo Fengqiong, Li Changlong, Zhu Tongbo
Department of Immunology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, 3-17 Renmin South Road, Chengdu, Sichuan 610041, PR China.
Department of Biochemistry, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, 3-17 Renmin South Road, Chengdu, Sichuan 610041, PR China.
Cell Signal. 2021 Oct;86:110115. doi: 10.1016/j.cellsig.2021.110115. Epub 2021 Aug 8.
To investigate the impact of oncogenic protein kinase C isoform ι (PKCι) on the microenvironment and the immunogenic properties of pancreatic tumors, we prohibit PKCι activity in various pancreatic ductal adenocarcinoma (PDAC) cell lines and co-culture them with human natural killer NK92 cells. The results demonstrate that PKCι 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 PKCι 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 PKCι in PDAC alleviates the immune suppression and enhances the cytotoxicity of NK92 towards PDAC through restraining PDL1 overexpression. Combined with PD1/PDL1 blocker, PKCι inhibitor remarkably elevates the cytotoxicity of NK92 against PDAC cells in vitro, establishing PKCι inhibitor as a promising candidate for boosting the immunotherapy of PDAC.
为了研究致癌蛋白激酶C同工型ι（PKCι）对胰腺肿瘤微环境和免疫原性的影响，我们在多种胰腺导管腺癌（PDAC）细胞系中抑制PKCι活性，并将它们与人自然杀伤细胞NK92共培养。结果表明，PKCι抑制增强了PDAC对NK细胞毒性的敏感性，并促进了共培养的NK92细胞的脱颗粒和溶细胞活性。机制研究指出，在KRAS下游，致癌性PKCι招募YAP1和STAT3以提高PDL1的表达，有助于在PDAC中构成免疫抑制微环境。与NK92共培养进一步通过STAT3诱导PDL1上调，以刺激PDAC细胞的免疫逃逸。随后，在PDAC中抑制PKCι可减轻免疫抑制，并通过抑制PDL1过表达增强NK92对PDAC的细胞毒性。与PD1/PDL1阻断剂联合使用时，PKCι抑制剂在体外显著提高NK92对PDAC细胞的细胞毒性，确立了PKCι抑制剂作为增强PDAC免疫治疗的有前景的候选药物。
