Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Department of Immunology, Leiden University Medical Centre, Leiden, the Netherlands.
Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands.
Cancer Cell. 2023 Jan 9;41(1):106-123.e10. doi: 10.1016/j.ccell.2022.11.014. Epub 2022 Dec 15.
Immune checkpoint blockade (ICB) has heralded a new era in cancer therapy. Research into the mechanisms underlying response to ICB has predominantly focused on T cells; however, effective immune responses require tightly regulated crosstalk between innate and adaptive immune cells. Here, we combine unbiased analysis of blood and tumors from metastatic breast cancer patients treated with ICB with mechanistic studies in mouse models of breast cancer. We observe an increase in systemic and intratumoral eosinophils in patients and mice responding to ICB treatment. Mechanistically, ICB increased IL-5 production by CD4 T cells, stimulating elevated eosinophil production from the bone marrow, leading to systemic eosinophil expansion. Additional induction of IL-33 by ICB-cisplatin combination or recombinant IL-33 promotes intratumoral eosinophil infiltration and eosinophil-dependent CD8 T cell activation to enhance ICB response. This work demonstrates the critical role of eosinophils in ICB response and provides proof-of-principle for eosinophil engagement to enhance ICB efficacy.
免疫检查点阻断（ICB）开创了癌症治疗的新时代。对 ICB 反应机制的研究主要集中在 T 细胞上；然而，有效的免疫反应需要先天免疫细胞和适应性免疫细胞之间的紧密调节的串扰。在这里，我们将接受 ICB 治疗的转移性乳腺癌患者的血液和肿瘤的无偏分析与乳腺癌小鼠模型中的机制研究相结合。我们观察到对 ICB 治疗有反应的患者和小鼠中全身和肿瘤内嗜酸性粒细胞的增加。从机制上讲，ICB 增加了 CD4 T 细胞产生的 IL-5，刺激骨髓中嗜酸性粒细胞的产生增加，导致全身嗜酸性粒细胞扩张。ICB-顺铂联合或重组 IL-33 的额外诱导促进了肿瘤内嗜酸性粒细胞浸润和嗜酸性粒细胞依赖性 CD8 T 细胞的激活，从而增强了 ICB 反应。这项工作证明了嗜酸性粒细胞在 ICB 反应中的关键作用，并为嗜酸性粒细胞的参与以增强 ICB 疗效提供了原理验证。
