Immune checkpoint blockade (ICB) has shown long-term survival benefits, but only in a small fraction of cancer patients. Recent studies suggest that improved vessel perfusion by ICB positively correlates with its therapeutic outcomes. However, the underlying mechanism of such a process remains unclear. Here, we show that anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) treatment-induced tumor vessel normalization was accompanied by an increased infiltration of eosinophils into breast tumors. Eosinophil accumulation was positively correlated with the responsiveness of a breast tumor to anti-CTLA4 therapy. Depletion of eosinophils subsequently negated vessel normalization, reduced antitumor immunity and attenuated tumor growth inhibition by anti-CTLA4 therapy. Moreover, intratumoral accumulation of eosinophils relied on T lymphocytes and interferon γ production. Together, these results suggest that eosinophils partially mediate the antitumor effects of CTLA4 blockade through vascular remodeling. Our findings uncover an unidentified role of eosinophils in anti-CTLA4 therapy, providing a potential new target to improve ICB therapy and to predict its efficacy.

中文翻译：

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CTLA4阻断通过嗜酸性粒细胞的积累促进乳腺肿瘤中的血管正常化。

免疫检查站封锁（ICB）已显示出长期生存益处，但仅在癌症患者中占一小部分。最近的研究表明，ICB改善的血管灌注与其治疗效果呈正相关。但是，这种过程的潜在机制仍不清楚。在这里，我们显示抗细胞毒性T淋巴细胞相关蛋白4（CTLA4）治疗诱导的肿瘤血管正常化伴随着嗜酸性粒细胞向乳腺肿瘤的浸润增加。嗜酸性粒细胞积累与乳腺肿瘤对抗CTLA4治疗的反应性呈正相关。嗜酸性粒细胞的耗竭随后使血管正常化，抗肿瘤免疫力降低和抗CTLA4治疗的肿瘤生长抑制作用减弱。而且，嗜酸性粒细胞的肿瘤内积累依赖于T淋巴细胞和干扰素γ的产生。总之，这些结果表明，嗜酸性粒细胞通过血管重塑部分介导了CTLA4阻断的抗肿瘤作用。我们的发现揭示了嗜酸性粒细胞在抗CTLA4治疗中的作用尚未确定，为改善ICB治疗和预测其疗效提供了潜在的新靶标。