Apolipoprotein E induces pathogenic senescent-like myeloid cells in prostate cancer
Apolipoprotein E induces pathogenic senescent-like myeloid cells in prostate cancer
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DOI：
10.1016/j.ccell.2023.02.004
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发表时间：
2023-03-13
期刊：
影响因子：
50.3
通讯作者：
Alimonti, Andrea
中科院分区：
文献类型：
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作者：
Bancaro, Nicolo;Cali, Bianca;Alimonti, Andrea
肿瘤细胞促进免疫抑制性中性粒细胞的募集，中性粒细胞是驱动免疫抑制、肿瘤增殖和治疗抗性的骨髓细胞亚群。在生理学上，已知中性粒细胞具有短的半衰期。在这里，我们报告了一个亚组的中性粒细胞的细胞衰老标志物的表达上调，并坚持在肿瘤微环境的鉴定。衰老样中性粒细胞表达髓样细胞上表达的触发受体2（TREM2），并且比典型的免疫抑制性中性粒细胞更具免疫抑制性和促肿瘤性。遗传和药理学消除衰老样中性粒细胞可降低不同前列腺癌小鼠模型的肿瘤进展。从机制上讲，我们发现前列腺肿瘤细胞分泌的载脂蛋白E（APOE）与中性粒细胞上的TREM2结合，促进其衰老。前列腺癌中APOE和TREM2表达增加，与预后不良相关。总的来说，这些结果揭示了肿瘤免疫逃避的另一种机制，并支持开发针对衰老样中性粒细胞的免疫衰老药物用于癌症治疗。
Tumor cells promote the recruitment of immunosuppressive neutrophils, a subset of myeloid cells driving im-mune suppression, tumor proliferation, and treatment resistance. Physiologically, neutrophils are known to have a short half-life. Here, we report the identification of a subset of neutrophils that have upregulated expression of cellular senescence markers and persist in the tumor microenvironment. Senescent-like neu-trophils express the triggering receptor expressed on myeloid cells 2 (TREM2) and are more immunosuppres-sive and tumor-promoting than canonical immunosuppressive neutrophils. Genetic and pharmacological elimination of senescent-like neutrophils decreases tumor progression in different mouse models of prostate cancer. Mechanistically, we have found that apolipoprotein E (APOE) secreted by prostate tumor cells binds TREM2 on neutrophils, promoting their senescence. APOE and TREM2 expression increases in prostate can-cers and correlates with poor prognosis. Collectively, these results reveal an alternative mechanism of tumor immune evasion and support the development of immune senolytics targeting senescent-like neutrophils for cancer therapy.