背景:乳腺癌是一种复杂的疾病,具有高度免疫抑制的肿瘤微环境,并且对免疫检查点阻断(ICB)治疗的临床反应有限。辅助性T细胞2(Th2),肿瘤微环境(TME)的重要组成部分,在调节肿瘤免疫中起着至关重要的作用。然而,Th2介导的免疫与乳腺癌免疫逃避之间的深层关系仍然是一个谜。
方法:这里,我们首先利用生物信息学分析来探讨Th2浸润与乳腺癌免疫景观的相关性。甲苯磺酸盐(IPD-1151T,IPD),Th2功能的抑制剂,然后用于研究Th2阻断对免疫活性小鼠乳腺癌模型中肿瘤生长和免疫微环境的生物学效应。通过流式细胞术分析肿瘤微环境,质量细胞计数,和免疫荧光染色。此外,我们通过评估TME检查了IPD联合ICB治疗的疗效,肿瘤生长和小鼠存活。
结果:我们的生物信息学分析表明,Th2细胞的较高浸润表明乳腺癌中存在肿瘤免疫抑制微环境。在三种小鼠乳腺癌模型(EO771,4T1和EMT6)中,IPD显著抑制Th2细胞分泌IL-4,提升了Th2到Th1的切换,重塑免疫景观,抑制肿瘤生长。值得注意的是,IPD治疗后,肿瘤组织中CD8T细胞浸润和细胞毒性T淋巴细胞(CTL)的细胞毒活性明显增强。此外,在IPD治疗的肿瘤中,效应CD4+T细胞增加,髓源性抑制细胞和M2样巨噬细胞减少.重要的是,我们发现IPD增强了ICB的治疗反应,而不增加潜在的不良反应.
结论:我们的研究结果表明,Th2细胞功能的药物抑制可通过重塑TME的免疫景观改善ICB反应,这说明了一种有前途的组合免疫疗法。
Breast 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.
Here, 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.
Our 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.
Our findings demonstrate that pharmaceutical inhibition of Th2 cell function improves ICB response via remodeling immune landscape of TME, which illustrates a promising combinatorial immunotherapy.