CTLA4 blockade promotes vessel normalization in breast tumors via the accumulation of eosinophils
CTLA4 blockade promotes vessel normalization in breast tumors via the accumulation of eosinophils
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DOI：
10.1002/ijc.32829
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发表时间：
2019-12
影响因子：
6.4
通讯作者：
Xichen Zheng;Naidong Zhang;Long Qian;Xuexiang Wang;P. Fan;Jiajie Kuai;Siyang Lin;Changpeng Liu;Wen Jiang;S. Qin;Haifeng Chen;Yuhui Huang
中科院分区：
文献类型：
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作者：
Xichen Zheng;Naidong Zhang;Long Qian;Xuexiang Wang;P. Fan;Jiajie Kuai;Siyang Lin;Changpeng Liu;Wen Jiang;S. Qin;Haifeng Chen;Yuhui Huang
免疫检查点阻断（ICB）已显示出长期生存益处，但仅适用于一小部分癌症患者。最近的研究表明，ICB改善血管灌注与其治疗结果呈正相关。然而，这一过程的基本机制仍不清楚。在这里，我们发现抗细胞毒性T淋巴细胞相关蛋白4（CTLA 4）治疗诱导的肿瘤血管正常化伴随着嗜酸性粒细胞浸润到乳腺肿瘤中的增加。嗜酸性粒细胞蓄积与乳腺肿瘤对抗CTLA 4治疗的反应性呈正相关。嗜酸性粒细胞的消耗随后否定了血管正常化，降低了抗肿瘤免疫力，并减弱了抗CTLA 4治疗对肿瘤生长的抑制作用。此外，肿瘤内嗜酸性粒细胞的积聚依赖于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CTLA 4阻断的抗肿瘤作用。我们的研究结果揭示了嗜酸性粒细胞在抗CTLA 4治疗中的未识别作用，为改善ICB治疗和预测其疗效提供了潜在的新靶点。
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.