The MYBL2–CCL2 axis promotes tumor progression and resistance to anti-PD-1 therapy in ovarian cancer by inducing immunosuppressive macrophages

Cancer Cell International

Research

Shuting Huang¹  Baoyue Pan²  Pingping Liu²  Xiaojing Zheng²  Mingxiu Ju²  Min Zheng²  Huiling Xiang²  ChunYan Lan²  Ting Wan²  Yinan Jiang²  Yun Zhou²  Jundong Li²  Linjing Yuan³  Rongzhen Luo⁴  Weihua Jia⁵ 

[1] Department of Gynecology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 510080, Guangzhou, China;Department of Gynecology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China;Department of Gynecology, The First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, China;Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 510060, Guangzhou, China;State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Biobank of Sun Yat-sen University Cancer Center, 510060, Guangzhou, China;

关键词: MYBL2;    Macrophages;    Ovarian cancer;    CCL2;   

DOI  :  10.1186/s12935-023-03079-2

 received in 2023-04-19, accepted in 2023-09-20,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundAn immunosuppressive tumor microenvironment in ovarian cancer facilitates tumor progression and resistance to immunotherapy. The function of MYB Proto-Oncogene Like 2 (MYBL2) in the tumor microenvironment remains largely unexplored.MethodsA syngeneic intraovarian mouse model, flow cytometry analysis, and immunohistochemistry were used to explore the biological function of MYBL2 in tumor progression and immune escape. Molecular and biochemical strategies—namely RNA-sequencing, western blotting, quantitative reverse transcription–polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay, multiplex immunofluorescence, chromatic immunoprecipitation assay (CHIP) and luciferase assay—were used to reveal the mechanisms of MYBL2 in the OVC microenvironment.ResultsWe found tumor derived MYBL2 indicated poor prognosis and selectively correlated with tumor associated macrophages (TAMs) in ovarian cancer. Mechanically, C-C motif chemokine ligand 2 (CCL2) transcriptionally activated by MYBL2 induced TAMs recruitment and M2-like polarization in vitro. Using a syngeneic intraovarian mouse model, we identified MYBL2 promoted tumor malignancyand increased tumor-infiltrating immunosuppressive macrophages. Cyclin-dependent kinase 2 (CDK2) was a known upstream kinase to phosphorylate MYBL2 and promote its transcriptional function. The upstream inhibitor of CDK2, CVT-313, reprogrammed the tumor microenvironment and reduced anti-PD-1 resistance.ConclusionsThe MYBL2/CCL2 axis contributing to TAMs recruitment and M2-like polarization is crucial to immune evasion and anti-PD-1 resistance in ovarian cancer, which is a potential target to enhance the efficacy of immunotherapy.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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