Tumor PKC delta instigates immune exclusion in EGFR-mutated non-small cell lung cancer

Zuo, Yi-Han1,2; Gao, Wei-Na1,3; Xie, Ya-Jia1; Yang, Sheng-Yong4,5; Zhou, Jin-Tai6; Liang, Hai-Hai7; Fan, Xing-Xing1

2022-12-08

10.1186/s12916-022-02670-0

BMC Medicine   Impact Factor & Quartile

1741-7015

BackgroundThe recruitment of a sufficient number of immune cells to induce an inflamed tumor microenvironment (TME) is a prerequisite for effective response to cancer immunotherapy. The immunological phenotypes in the TME of EGFR-mutated lung cancer were characterized as non-inflamed, for which immunotherapy is largely ineffective. MethodsGlobal proteomic and phosphoproteomic data from lung cancer tissues were analyzed aiming to map proteins related to non-inflamed TME. The ex vivo and in vivo studies were carried out to evaluate the anti-tumor effect. Proteomics was applied to identify the potential target and signaling pathways. CRISPR-Cas9 was used to knock out target genes. The changes of immune cells were monitored by flow cytometry. The correlation between PKC delta and PD-L1 was verified by clinical samples. ResultsWe proposed that PKC delta, a gatekeeper of immune homeostasis with kinase activity, is responsible for the un-inflamed phenotype in EGFR-mutated lung tumors. It promotes tumor progression by stimulating extracellular matrix (ECM) and PD-L1 expression which leads to immune exclusion and assists cancer cell escape from T cell surveillance. Ablation of PKC delta enhances the intratumoral penetration of T cells and suppresses the growth of tumors. Furthermore, blocking PKC delta significantly sensitizes the tumor to immune checkpoint blockade (ICB) therapy (alpha PD-1) in vitro and in vivo model. ConclusionsThese findings revealed that PKC delta is a critical switch to induce inflamed tumors and consequently enhances the efficacy of ICB therapy in EGFR-mutated lung cancer. This opens a new avenue for applying immunotherapy against recalcitrant tumors.

Tumor microenvironment Immune checkpoint Tumor infiltrating lymphocytes PKC delta PD-1

SCI

English

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Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery["0003/2018/A1","0058/2020/A2"] ; [001/2020/ALC]

General & Internal Medicine

Medicine, General & Internal

WOS:000895935400003

BMC

Web of Science

1.Macau Univ Sci & Technol, Dr Nehers Biophys Lab Innovat Drug Discovery, State Key Lab Qual Res Chinese Med, Macau, Peoples R China
2.Harvard Med Sch, Dept Cardiol, Boston, MA USA
3.Southern Univ Sci & Technol, Dept Chem, Shenzhen, Guangdong, Peoples R China
4.Sichuan Univ, State Key Lab Biotherapy, Chengdu, Peoples R China
5.Sichuan Univ, West China Hosp, Canc Ctr, West China Med Sch, Chengdu, Peoples R China
6.TianJin Med Univ, Gen Hosp, Tianjin, Peoples R China
7.Harbin Med Univ, Coll Pharm, Dept Pharmacol, Harbin, Heilongjiang, Peoples R China

Zuo, Yi-Han,Gao, Wei-Na,Xie, Ya-Jia,et al. Tumor PKC delta instigates immune exclusion in EGFR-mutated non-small cell lung cancer[J]. BMC Medicine,2022,20(1).

Zuo, Yi-Han.,Gao, Wei-Na.,Xie, Ya-Jia.,Yang, Sheng-Yong.,Zhou, Jin-Tai.,...&Fan, Xing-Xing.(2022).Tumor PKC delta instigates immune exclusion in EGFR-mutated non-small cell lung cancer.BMC Medicine,20(1).

Zuo, Yi-Han,et al."Tumor PKC delta instigates immune exclusion in EGFR-mutated non-small cell lung cancer".BMC Medicine 20.1(2022).