Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
J Transl Med. 2022 Dec 23;20(1):615. doi: 10.1186/s12967-022-03807-8.
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.
乳腺癌是一种复杂的疾病，其肿瘤微环境具有高度免疫抑制性，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）细胞是肿瘤微环境（TME）的重要组成部分，在调节肿瘤免疫方面发挥着重要作用。然而，Th2 介导的免疫与乳腺癌中的免疫逃逸之间的深层关系仍然是个谜。
我们首先使用生物信息学分析来探索 Th2 浸润与乳腺癌免疫景观之间的相关性。然后，我们使用 Th2 功能抑制剂舒拉明来研究 Th2 阻断对免疫功能正常的小鼠乳腺癌模型中肿瘤生长和免疫微环境的生物学影响。通过流式细胞术、质谱细胞术和免疫荧光染色分析肿瘤微环境。此外，我们通过评估 TME、肿瘤生长和小鼠生存来检查 IPD 与 ICB 联合治疗的疗效。
我们的生物信息学分析表明，Th2 细胞浸润较高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 显著抑制了 Th2 细胞的 IL-4 分泌，促进了 Th2 向 Th1 的转化，重塑了免疫景观并抑制了肿瘤生长。值得注意的是，IPD 治疗后肿瘤组织中 CD8 T 细胞浸润和细胞毒性 T 淋巴细胞（CTL）的细胞毒性明显增强。此外，还在 IPD 治疗的肿瘤中观察到效应性 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，而没有增加潜在的不良反应。
我们的研究结果表明，通过重塑 TME 的免疫景观，药物抑制 Th2 细胞功能可改善 ICB 反应，这说明了一种有前途的联合免疫疗法。
