Epigenetic reprogramming of Runx3 reinforces CD8 + T-cell function and improves the clinical response to immunotherapy

Molecular Cancer

Research

Dongrui Wang¹  Yibo Gao²  Jie He²  Yating Feng²  Yingli Sun³  Zongzhi Liu⁴  Yang Liu⁵  Qian Mei⁵  Xiang Li⁵  Jiejie Liu⁵  Chunmeng Wang⁵  Weidong Han⁵  Junyun Wang⁶ 

[1] Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, 310058, Hangzhou, China;Liangzhu Laboratory, Zhejiang University Medical Center, 310058, Hangzhou, China;Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academic of Medical Sciences and Peking Union Medical College, 518116, Shenzhen, China;Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academic of Medical Sciences and Peking Union Medical College, 518116, Shenzhen, China;Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, 100101, Beijing, China;Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academic of Medical Sciences and Peking Union Medical College, 518116, Shenzhen, China;Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, 100101, Beijing, China;Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, 518055, Shenzhen, China;University of Chinese Academy of Sciences, 100049, Beijing, China;Changping Laboratory, Yard 28, Science Park Road, Changping District, 102206, Beijing, China;Changping Laboratory, Yard 28, Science Park Road, Changping District, 102206, Beijing, China;Department of Bio-therapeutic, the First Medical Center, Chinese PLA General Hospital, Beijing, China;Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, 100101, Beijing, China;University of Chinese Academy of Sciences, 100049, Beijing, China;

关键词: ;   

DOI  :  10.1186/s12943-023-01768-0

 received in 2022-12-15, accepted in 2023-03-24,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundCheckpoint blockade immunotherapy, represented by PD-1 or PD-L1 antibody treatment, has been of tremendous success in clinical practice. However, the low clinical response rate and lack of biomarkers for prediction of the immune response limit the clinical application of anti-PD-1 immunotherapy. Our recent work showed that a combination of low-dose decitabine and PD-1-ab significantly improved the complete response (CR) rate of cHL patients from 32 to 71%, which indicates that there is a significant correlation between epigenetic regulation and the clinical response to immunotherapy.MethodsWe recruited two groups of Hodgkin lymphoma patients who were treated with anti-PD-1 and DAC+anti-PD-1. CD8+ T cells were isolated from the patients' peripheral blood, DNA methylation was analyzed by EPIC, the expression profile was analyzed by RNA-seq, and multigroup analysis was performed with IPA and GSEA functional annotations. We explored the effect of DAC on the function of CD8+ T cells in the blood, spleen, tumor and lymph nodes using a mouse model. Furthermore, we explored the function of Tils in the tumor microenvironment. Then, we constructed Runx3-knockout mice to confirm the T-cell-specific function of Runx3 in CD8+ T cells and analyzed various subtypes of T cells and cytokines using mass cytometry (CyTOF).ResultsMultiomics analysis identified that DNA methylation reprogramming of Runx3 was a crucial mediator of CD8+ T-cell function. Multiomics data showed that reversal of methylation of the Runx3 promoter promoted the infiltration of CD8+ TILs and mitigated the exhaustion of CD8+ T cells. Furthermore, experiments on tissue-specific Runx3-knockout mice showed that Runx3 deficiency reduced CD8+ T infiltration and the differentiation of effector T and memory T cells. Furthermore, Runx3 deficiency significantly decreased CCR3 and CCR5 levels. Immunotherapy experiments in Runx3 conditional knockout mice showed that DAC could not reverse the resistance of anti-PD-1 in the absence of Runx3. Moreover, both our clinical data and data from TISIDB showed that Runx3 could be a potential biomarker for immunotherapy to predict the clinical response rate.ConclusionWe demonstrate that the DNA methylation of Runx3 plays a critical role in CD8+ T-cell infiltration and differentiation during decitabine-primed PD-1-ab immunotherapy, which provides a supporting mechanism for the essential role of epiregulation in immunotherapy.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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