Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Department of Pathology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Cancer Res. 2021 Nov 1;81(21):5555-5571. doi: 10.1158/0008-5472.CAN-21-0839. Epub 2021 Aug 24.
The recognition of the immune system as a key component of the tumor microenvironment (TME) led to promising therapeutics. Because such therapies benefit only subsets of patients, understanding the activities of immune cells in the TME is required. Eosinophils are an integral part of the TME especially in mucosal tumors. Nonetheless, their role in the TME and the environmental cues that direct their activities are largely unknown. We report that breast cancer lung metastases are characterized by resident and recruited eosinophils. Eosinophil recruitment to the metastatic sites in the lung was regulated by G protein-coupled receptor signaling but independent of CCR3. Functionally, eosinophils promoted lymphocyte-mediated antitumor immunity. Transcriptome and proteomic analyses identified the TME rather than intrinsic differences between eosinophil subsets as a key instructing factor directing antitumorigenic eosinophil activities. Specifically, TNFα/IFNγ-activated eosinophils facilitated CD4 and CD8 T-cell infiltration and promoted antitumor immunity. Collectively, we identify a mechanism by which the TME trains eosinophils to adopt antitumorigenic properties, which may lead to the development of eosinophil-targeted therapeutics. SIGNIFICANCE: These findings demonstrate antitumor activities of eosinophils in the metastatic tumor microenvironment, suggesting that harnessing eosinophil activity may be a viable clinical strategy in patients with cancer.
免疫系统被认为是肿瘤微环境（TME）的关键组成部分，这为癌症治疗带来了新的希望。但由于此类疗法仅对部分患者有效，因此需要了解 TME 中免疫细胞的活动。嗜酸性粒细胞是 TME 的重要组成部分，尤其在黏膜肿瘤中。然而，它们在 TME 中的作用以及指导其活动的环境线索在很大程度上仍是未知的。我们报告称，乳腺癌肺转移灶中存在固有和募集的嗜酸性粒细胞。嗜酸性粒细胞向肺部转移部位的募集受到 G 蛋白偶联受体信号的调节，但不依赖于 CCR3。功能上，嗜酸性粒细胞促进了淋巴细胞介导的抗肿瘤免疫。转录组和蛋白质组分析表明，TME 而不是嗜酸性粒细胞亚群之间的内在差异是指导抗肿瘤嗜酸性粒细胞活性的关键指示因素。具体来说，TNFα/IFNγ 激活的嗜酸性粒细胞促进了 CD4 和 CD8 T 细胞的浸润，并促进了抗肿瘤免疫。总的来说，我们确定了一种机制，即 TME 使嗜酸性粒细胞获得抗肿瘤特性，这可能会促使开发针对嗜酸性粒细胞的治疗方法。意义：这些发现表明嗜酸性粒细胞在转移性肿瘤微环境中具有抗肿瘤活性，这表明利用嗜酸性粒细胞的活性可能是癌症患者的一种可行的临床策略。
