PO.IM02.06 · 免疫学
尿路上皮癌中肿瘤相关白细胞增多的多组学解析鉴定出 IL13RA2 为关键驱动因素
Multi-omics dissection of tumor-related leukocytosis in urothelial carcinoma identifies IL13RA2 as a key driver
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：
肿瘤相关白细胞增多（TRL）主要由中性粒细胞过度产生驱动，在多种实体瘤中与疾病侵袭性、治疗耐药及不良生存相关。在转移性尿路上皮癌（mUC）中，伴有 TRL 的患者在接受免疫检查点抑制剂（ICI）治疗时预后尤其差，提示存在免疫抑制性肿瘤微环境。然而，将 TRL 与 ICI 耐药相联系的分子基础仍不明确。
方法：
我们回顾性评估了接受 ICI 治疗的 mUC 患者，以评估 TRL 的预后作用。对 35 例肿瘤的 RNA 进行 NanoString 分析以鉴定白细胞增多相关基因。通过 qPCR、蛋白质印迹以及包括增殖、迁移、细胞因子分析和中性粒细胞趋化在内的功能实验，在多个 UC 细胞系中验证了 IL13RA2 及相关候选基因。使用 Clariom S 微阵列定义由 IL13RA2 调控的转录程序。
结果：
基线白细胞增多（WBC >10,000/µL）的患者总生存显著更差，确认 TRL 在 ICI 治疗期间是一个负向预后因素。高 WBC 肿瘤显示出独特的炎症特征，其中 IL13RA2 是上调最显著的基因之一。IL13RA2 表达在 TCGA BLCA 中与中性粒细胞富集强烈相关（Pearson r = 0.41；TIMER ρ = 0.199），并在接受 ICI 治疗的 GSE176307 队列中得到验证，其中 IL13RA2 高表达肿瘤显示出中性粒细胞和髓系细胞比例增加。在功能上，IL13RA2 敲低降低了 UMUC3 和 T24 细胞的增殖、迁移和创伤愈合能力。微阵列分析鉴定出可重复的 IL13RA2 调控基因集，富集于细胞因子、炎症、运动和趋化途径。IL13RA2 表达细胞的条件培养基强烈诱导纯化中性粒细胞的迁移，而 IL13RA2 缺失则显著削弱中性粒细胞趋化。IL13RA2 沉默抑制 JAK1/2-STAT3 活性，并降低多种促炎细胞因子和趋化因子，包括 CXCL5、CXCL6、CXCL8、CCL3 和 CCL4。
结论：
TRL 是 ICI 治疗的 mUC 中一个强有力的负向预后因素。IL13RA2 通过促进炎症信号、细胞因子产生和髓系细胞招募，成为将白细胞增多与免疫耐药相联系的核心驱动因素。这些发现确立 IL13RA2 为 TRL 的关键介导因子，以及克服尿路上皮癌中髓系细胞驱动的 ICI 耐药的潜在治疗靶点。
查看英文原文 English abstract
Background:
Tumor-related leukocytosis (TRL), driven largely by neutrophil overproduction, is associated with aggressive disease, treatment resistance, and poor survival across solid tumors. In metastatic urothelial carcinoma (mUC), patients with TRL experience particularly poor outcomes under immune checkpoint inhibitor (ICI) therapy, suggesting an immune-suppressive tumor microenvironment. However, the molecular basis linking TRL to ICI resistance remains unclear.
Methods:
We retrospectively evaluated mUC patients receiving ICIs to assess the prognostic role of TRL. RNA from 35 tumors underwent NanoString profiling to identify leukocytosis-associated genes. IL13RA2 and related candidates were validated across UC cell lines by qPCR, western blotting, and functional assays including proliferation, migration, cytokine analysis, and neutrophil chemotaxis. Transcriptional programs regulated by IL13RA2 were defined using Clariom S microarray.
Results:
Patients with baseline leukocytosis (WBC >10,000/µL) showed significantly worse overall survival, confirming TRL as a negative prognostic factor during ICI therapy. High-WBC tumors displayed a distinct inflammatory signature, with IL13RA2 among the most upregulated genes. IL13RA2 expression strongly associated with neutrophil enrichment in TCGA BLCA (Pearson r = 0.41; TIMER ρ = 0.199) and was validated in the ICI-treated GSE176307 cohort, where IL13RA2-high tumors exhibited increased neutrophil and myeloid fractions. Functionally, IL13RA2 knockdown reduced proliferation, migration, and wound-healing capacity in UMUC3 and T24 cells. Microarray analysis identified reproducible IL13RA2-regulated gene sets enriched for cytokine, inflammatory, motility, and chemotaxis pathways. Conditioned media from IL13RA2-expressing cells robustly induced migration of purified neutrophils, whereas IL13RA2 depletion markedly impaired neutrophil chemotaxis. IL13RA2 silencing suppressed JAK1/2-STAT3 activity and reduced multiple pro-inflammatory cytokines and chemokines, including CXCL5, CXCL6, CXCL8, CCL3, and CCL4.
Conclusions:
TRL is a potent negative prognostic factor in ICI-treated mUC. IL13RA2 emerges as a central driver linking leukocytosis to immune resistance by promoting inflammatory signaling, cytokine production, and myeloid recruitment. These findings identify IL13RA2 as a key mediator of TRL and a potential therapeutic target to overcome myeloid-driven ICI resistance in urothelial carcinoma.
利益披露 Disclosure
H. Su,
Merck KGaA Travel, Support for AACR 2025 annual meeting.
Takeda Travel, support for ESMO meeting 2025.
M. Kuo, None..
H. Huang, None..
C. Chien, None.