Pharmaceutical targeting Th2-mediated immunity enhances immunotherapy response in breast cancer

Journal of Translational Medicine

Research

Hongzhong Li¹  Jiazhou Liu¹  Yuru Chen¹  Guosheng Ren¹  Xiaoyu Wang¹  Rui Feng¹  Jiazheng Sun¹  Jinxiang Tan²  Xiaoyi Wang²  Qin Li³  Huimin Du⁴  Yachan Luo⁵  Jing Huang⁶ 

[1] Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China;Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China;Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China;Department of Oncology, Beijing Friendship Hospital, Capital Medical University, 100050, Beijing, China;Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China;Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China;Department of Respiratory, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China;

关键词: Th2 cell;    Suplatast tosilate;    Breast cancer;    Immune checkpoint blockade;    Immunotherapy;   

DOI  :  10.1186/s12967-022-03807-8

 received in 2022-10-21, accepted in 2022-12-02,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundBreast cancer is a complex disease with a highly immunosuppressive tumor microenvironment, and has limited clinical response to immune checkpoint blockade (ICB) therapy. T-helper 2 (Th2) cells, an important component of the tumor microenvironment (TME), play an essential role in regulation of tumor immunity. However, the deep relationship between Th2-mediated immunity and immune evasion in breast cancer remains enigmatic.MethodsHere, we first used bioinformatics analysis to explore the correlation between Th2 infiltration and immune landscape in breast cancer. Suplatast tosilate (IPD-1151 T, IPD), an inhibitor of Th2 function, was then employed to investigate the biological effects of Th2 blockade on tumor growth and immune microenvironment in immunocompetent murine breast cancer models. The tumor microenvironment was analyzed by flow cytometry, mass cytometry, and immunofluorescence staining. Furthermore, we examined the efficacy of IPD combination with ICB treatment by evaluating TME, tumor growth and mice survival.ResultsOur bioinformatics analysis suggested that higher infiltration of Th2 cells indicates a tumor immunosuppressive microenvironment in breast cancer. In three murine breast cancer models (EO771, 4T1 and EMT6), IPD significantly inhibited the IL-4 secretion by Th2 cells, promoted Th2 to Th1 switching, remodeled the immune landscape and inhibited tumor growth. Remarkably, CD8+ T cell infiltration and the cytotoxic activity of cytotoxic T lymphocyte (CTL) in tumor tissues were evidently enhanced after IPD treatment. Furthermore, increased effector CD4+ T cells and decreased myeloid-derived suppressor cells and M2-like macrophages were also demonstrated in IPD-treated tumors. Importantly, we found IPD reinforced the therapeutic response of ICB without increasing potential adverse effects.ConclusionsOur findings demonstrate that pharmaceutical inhibition of Th2 cell function improves ICB response via remodeling immune landscape of TME, which illustrates a promising combinatorial immunotherapy.

【 授权许可】

CC BY   
© The Author(s) 2022

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