Glycolytic neutrophils accrued in the spleen compromise anti-tumour T cell immunity in breast cancer
Glycolytic neutrophils accrued in the spleen compromise anti-tumour T cell immunity in breast cancer
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DOI：
10.1038/s42255-023-00853-4
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发表时间：
2023-08
影响因子：
20.8
通讯作者：
Yu Wang;Muhan Xu;Jian-Fu Sun;Xiaoxiao Li;Huazheng Shi;Xuefeng Wang;Benming Liu;Zhang Tao;Xuanwei Jiang;Liangyu Lin;Qing Li;Yin Huang;Yong Liang;Mingyuan Hu;Fanjun Zheng;Fengyu Zhang;Jian Sun;Yufang Shi;Ying Wang
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文献类型：
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作者：
Yu Wang;Muhan Xu;Jian-Fu Sun;Xiaoxiao Li;Huazheng Shi;Xuefeng Wang;Benming Liu;Zhang Tao;Xuanwei Jiang;Liangyu Lin;Qing Li;Yin Huang;Yong Liang;Mingyuan Hu;Fanjun Zheng;Fengyu Zhang;Jian Sun;Yufang Shi;Ying Wang
器官间免疫力的协调对于癌症的发展和进展至关重要。众所周知，肿瘤中不利的代谢微环境是有效抗肿瘤免疫的主要障碍。然而，肿瘤以外的次级淋巴组织中的代谢改变是否会影响抗肿瘤免疫仍然难以捉摸。使用正电子发射断层扫描-计算机断层扫描，我们发现，人类和小鼠的脾脏与乳腺癌的代谢重新编程糖酵解状态。脾中葡萄糖消耗的这种增加主要发生在髓外造血和从骨髓募集产生的中性粒细胞中。白色髓中的这些嗜中性粒细胞产生葡萄糖缺乏的微环境，这反过来又通过损害丙酮酸激酶M2及其对STAT 5的作用诱导T细胞无反应性，从而损害其抗肿瘤活性。此外，由脾基质细胞产生的CCL 9趋化因子是脾中性粒细胞积聚的中心，并且CCR 1受体的阻断有利于肿瘤根除。因此，中性粒细胞在代谢上影响脾脏微环境并控制抗肿瘤T细胞反应。
The coordination of immunity across organs is fundamental to cancer development and progression. It is well known that the hostile metabolic microenvironment in the tumour is a major obstacle to effective anti-tumour immunity. However, whether metabolic alterations in secondary lymphoid tissues beyond the tumour can affect anti-tumour immunity remains elusive. Using positron-emission tomography–computed tomography, we show that the spleens of humans and mice with breast cancer are metabolically reprogrammed to a glycolytic state. Such an increase in glucose consumption in the spleen primarily occurs in neutrophils generated by extramedullary haematopoiesis and recruitment from the bone marrow. These neutrophils in the white pulp create a glucose-deprived microenvironment, which, in turn, induces T cell anergy by impairing pyruvate kinase M2 and its action on STAT5, thus compromising their anti-tumour activities. Furthermore, CCL9 chemokine produced by splenic stromal cells is central to splenic neutrophil accumulation, and blockade of the CCR1 receptor favours tumour eradication. Thus, neutrophils metabolically influence the spleen microenvironment and control anti-tumour T cell responses.