KLF5 inhibition potentiates anti-PD1 efficacy by enhancing CD8+T-cell-dependent antitumor immunity

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	KLF5 inhibition potentiates anti-PD1 efficacy by enhancing CD8+T-cell-dependent antitumor immunity
	Wu, Q; Liu, Z; Gao, ZJ; Luo, Y; Li, FB; Yang, CY; Wang, TT; Meng, XY; Chen, HJ; Li, JJ; Kong, YJ; Dong, C; Sun, S; Chen, CS
	2023
发表期刊	THERANOSTICS
ISSN	1838-7640
卷号	13 期号:4 页码:1381-1400
摘要	Background: Immune checkpoint blockers (ICBs) are revolutionized therapeutic strategies for cancer, but most patients with solid neoplasms remain resistant to ICBs, partly because of the difficulty in reversing the highly immunosuppressive tumor microenvironment (TME). Exploring the strategies for tumor immunotherapy is highly dependent on the discovery of molecular mechanisms of tumor immune escape and potential therapeutic target. Kruppel-like Factor 5 (KLF5) is a cell-intrinsic oncogene to promote tumorigenesis. However, the cell-extrinsic effects of KLF5 on suppressing the immune response to cancer remain unclear. Methods: We analyzed the immunosuppressive role of KLF5 in mice models transplanted with KLF5-deleted/overexpressing tumor cells. We performed RNA sequencing, immunohistochemistry, western blotting, real time-PCR, ELISA, luciferase assay, chromatin immunoprecipitation (ChIP), and flow cytometry to demonstrate the effects of KLF5 on CD8+ T cell infiltration and related molecular mechanism. Single-cell RNA sequencing and spatial transcriptomics analysis were applied to further decipher the association between KLF5 expression and infiltrating immune cells. The efficacy of KLF5/COX2 inhibitors combined with anti-programmed cell death protein 1 (anti-PD1) therapy were explored in pre-clinical models. Finally, a gene-expression signature depending on KLF5/COX2 axis and associated immune markers was created to predict patient survival. Results: KLF5 inactivation decelerated basal-like breast tumor growth in a CD8+ T-cell-dependent manner. Transcriptomic profiling revealed that KLF5 loss in tumors increases the number and activated function of T lymphocytes. Mechanistically, KLF5 binds to the promoter of the COX2 gene and promotes COX2 transcription; subsequently, KLF5 deficiency decreases prostaglandin E2 (PGE2) release from tumor cells by reducing COX2 expression. Inhibition of the KLF5/COX2 axis increases the number and functionality of intratumoral antitumor T cells to synergize the antitumorigenic effects of anti-PD1 therapy. Analysis of patient datasets at single-cell and spatial resolution shows that low expression of KLF5 is associated with an immune-supportive TME. Finally, we generate a KLF5/COX2-associated immune score (KC-IS) to predict patient survival. Conclusions: Our results identified a novel mechanism responsible for KLF5-mediated immunosuppression in TME, and targeting the KLF5/COX2/PGE2 axis is a critical immunotherapy sensitizer.
收录类别	SCI
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/14187
专题	科研部门_肿瘤生物学（陈策实）
推荐引用方式 GB/T 7714	Wu, Q,Liu, Z,Gao, ZJ,et al. KLF5 inhibition potentiates anti-PD1 efficacy by enhancing CD8+T-cell-dependent antitumor immunity[J]. THERANOSTICS,2023,13(4):1381-1400.
APA	Wu, Q.,Liu, Z.,Gao, ZJ.,Luo, Y.,Li, FB.,...&Chen, CS.(2023).KLF5 inhibition potentiates anti-PD1 efficacy by enhancing CD8+T-cell-dependent antitumor immunity.THERANOSTICS,13(4),1381-1400.
MLA	Wu, Q,et al."KLF5 inhibition potentiates anti-PD1 efficacy by enhancing CD8+T-cell-dependent antitumor immunity".THERANOSTICS 13.4(2023):1381-1400.

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