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肿瘤与中性粒细胞的相互作用调控肿瘤微环境，决定膀胱癌的进展。

Tumor-neutrophil cross talk orchestrates the tumor microenvironment to determine the bladder cancer progression.

机构信息

Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, China.

Department of Pediatric Surgery, Qilu Hospital Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, China.

出版信息

Proc Natl Acad Sci U S A. 2024 May 14;121(20):e2312855121. doi: 10.1073/pnas.2312855121. Epub 2024 May 7.

DOI:10.1073/pnas.2312855121
PMID:38713626
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11098120/
Abstract

The immune landscape of bladder cancer progression is not fully understood, and effective therapies are lacking in advanced bladder cancer. Here, we visualized that bladder cancer cells recruited neutrophils by secreting interleukin-8 (IL-8); in turn, neutrophils played dual functions in bladder cancer, including hepatocyte growth factor (HGF) release and CCL3PD-L1 super-immunosuppressive subset formation. Mechanistically, c-Fos was identified as the mediator of HGF up-regulating IL-8 transcription in bladder cancer cells, which was central to the positive feedback of neutrophil recruitment. Clinically, compared with serum IL-8, urine IL-8 was a better biomarker for bladder cancer prognosis and clinical benefit of immune checkpoint blockade (ICB). Additionally, targeting neutrophils or hepatocyte growth factor receptor (MET) signaling combined with ICB inhibited bladder cancer progression and boosted the antitumor effect of CD8 T cells in mice. These findings reveal the mechanism by which tumor-neutrophil cross talk orchestrates the bladder cancer microenvironment and provide combination strategies, which may have broad impacts on patients suffering from malignancies enriched with neutrophils.

摘要

膀胱癌进展的免疫景观尚不完全清楚，晚期膀胱癌缺乏有效的治疗方法。在这里，我们观察到膀胱癌细胞通过分泌白细胞介素-8 (IL-8) 招募中性粒细胞；反过来，中性粒细胞在膀胱癌中发挥双重作用，包括肝细胞生长因子 (HGF) 释放和 CCL3PD-L1 超级免疫抑制亚群形成。从机制上讲，c-Fos 被确定为 HGF 在膀胱癌细胞中上调 IL-8 转录的介质，这是中性粒细胞募集正反馈的核心。临床上，与血清 IL-8 相比，尿液 IL-8 是膀胱癌预后和免疫检查点阻断 (ICB) 临床获益的更好生物标志物。此外，靶向中性粒细胞或肝细胞生长因子受体 (MET) 信号联合 ICB 抑制了膀胱癌的进展，并增强了 CD8 T 细胞在小鼠中的抗肿瘤作用。这些发现揭示了肿瘤-中性粒细胞相互作用协调膀胱癌微环境的机制，并提供了联合策略，可能对富含中性粒细胞的恶性肿瘤患者产生广泛影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202f/11098120/8f5d5377a001/pnas.2312855121fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202f/11098120/c85e9c8155c1/pnas.2312855121fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202f/11098120/58b37fe735d8/pnas.2312855121fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202f/11098120/38ec2450317b/pnas.2312855121fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202f/11098120/c0e74ba92dd4/pnas.2312855121fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202f/11098120/f3d9e39a55fc/pnas.2312855121fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202f/11098120/8f5d5377a001/pnas.2312855121fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202f/11098120/c85e9c8155c1/pnas.2312855121fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202f/11098120/58b37fe735d8/pnas.2312855121fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202f/11098120/38ec2450317b/pnas.2312855121fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202f/11098120/c0e74ba92dd4/pnas.2312855121fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202f/11098120/f3d9e39a55fc/pnas.2312855121fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202f/11098120/8f5d5377a001/pnas.2312855121fig06.jpg

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