Tumor PKCδ instigates immune exclusion in EGFR-mutated non–small cell lung cancer
Abstract Background The 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...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-12-01
|
| Series: | BMC Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12916-022-02670-0 |
| _version_ | 1811188234080747520 |
|---|---|
| author | Yi-Han Zuo Wei-Na Gao Ya-Jia Xie Sheng-Yong Yang Jin-Tai Zhou Hai-Hai Liang Xing-Xing Fan |
| author_facet | Yi-Han Zuo Wei-Na Gao Ya-Jia Xie Sheng-Yong Yang Jin-Tai Zhou Hai-Hai Liang Xing-Xing Fan |
| author_sort | Yi-Han Zuo |
| collection | DOAJ |
| description | Abstract Background The 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. Methods Global 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 PKCδ and PD-L1 was verified by clinical samples. Results We proposed that PKCδ, 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 PKCδ enhances the intratumoral penetration of T cells and suppresses the growth of tumors. Furthermore, blocking PKCδ significantly sensitizes the tumor to immune checkpoint blockade (ICB) therapy (αPD-1) in vitro and in vivo model. Conclusions These findings revealed that PKCδ 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. Graphical Abstract |
| first_indexed | 2024-04-11T14:16:09Z |
| format | Article |
| id | doaj.art-c43ceff5c9044977bfd37e4e9852961d |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-04-11T14:16:09Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-c43ceff5c9044977bfd37e4e9852961d2022-12-22T04:19:25ZengBMCBMC Medicine1741-70152022-12-0120111410.1186/s12916-022-02670-0Tumor PKCδ instigates immune exclusion in EGFR-mutated non–small cell lung cancerYi-Han Zuo0Wei-Na Gao1Ya-Jia Xie2Sheng-Yong Yang3Jin-Tai Zhou4Hai-Hai Liang5Xing-Xing Fan6Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan UniversityTianJin Medical University General HospitalDepartment of Pharmacology, College of Pharmacy, Harbin Medical UniversityDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyAbstract Background The 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. Methods Global 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 PKCδ and PD-L1 was verified by clinical samples. Results We proposed that PKCδ, 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 PKCδ enhances the intratumoral penetration of T cells and suppresses the growth of tumors. Furthermore, blocking PKCδ significantly sensitizes the tumor to immune checkpoint blockade (ICB) therapy (αPD-1) in vitro and in vivo model. Conclusions These findings revealed that PKCδ 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. Graphical Abstracthttps://doi.org/10.1186/s12916-022-02670-0Tumor microenvironmentImmune checkpointTumor infiltrating lymphocytesPKCδPD-1 |
| spellingShingle | Yi-Han Zuo Wei-Na Gao Ya-Jia Xie Sheng-Yong Yang Jin-Tai Zhou Hai-Hai Liang Xing-Xing Fan Tumor PKCδ instigates immune exclusion in EGFR-mutated non–small cell lung cancer BMC Medicine Tumor microenvironment Immune checkpoint Tumor infiltrating lymphocytes PKCδ PD-1 |
| title | Tumor PKCδ instigates immune exclusion in EGFR-mutated non–small cell lung cancer |
| title_full | Tumor PKCδ instigates immune exclusion in EGFR-mutated non–small cell lung cancer |
| title_fullStr | Tumor PKCδ instigates immune exclusion in EGFR-mutated non–small cell lung cancer |
| title_full_unstemmed | Tumor PKCδ instigates immune exclusion in EGFR-mutated non–small cell lung cancer |
| title_short | Tumor PKCδ instigates immune exclusion in EGFR-mutated non–small cell lung cancer |
| title_sort | tumor pkcδ instigates immune exclusion in egfr mutated non small cell lung cancer |
| topic | Tumor microenvironment Immune checkpoint Tumor infiltrating lymphocytes PKCδ PD-1 |
| url | https://doi.org/10.1186/s12916-022-02670-0 |
| work_keys_str_mv | AT yihanzuo tumorpkcdinstigatesimmuneexclusioninegfrmutatednonsmallcelllungcancer AT weinagao tumorpkcdinstigatesimmuneexclusioninegfrmutatednonsmallcelllungcancer AT yajiaxie tumorpkcdinstigatesimmuneexclusioninegfrmutatednonsmallcelllungcancer AT shengyongyang tumorpkcdinstigatesimmuneexclusioninegfrmutatednonsmallcelllungcancer AT jintaizhou tumorpkcdinstigatesimmuneexclusioninegfrmutatednonsmallcelllungcancer AT haihailiang tumorpkcdinstigatesimmuneexclusioninegfrmutatednonsmallcelllungcancer AT xingxingfan tumorpkcdinstigatesimmuneexclusioninegfrmutatednonsmallcelllungcancer |