PO.TB10.03 · 肿瘤生物学

高表达CXCL2的中性粒细胞样单核细胞（NeuMos）协调全身粒细胞生成并驱动TNBC免疫治疗耐药

Neutrophil-like monocytes (NeuMos) with high levels of CXCL2 expression orchestrate systemic granulopoiesis and drive immunotherapy resistance in TNBC

编号 3431 展板 3 时间 4/20 02:00–05:00 区域 Section 29 主讲 Fulya Alkan, BS;MS;PhD

分会场 Microenvironmental Determinants of Therapy Response and Resistance 1

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作者与单位 Authors & Affiliations

Fulya Alkan¹, Hilmi K. Alkan¹, Ahmet Caglayan², Aysun Caglayan², Aminah Lawal³, Neva Celiker³, Huidong Shi⁴, Thomas Vogl⁵, Nouri Neamati⁶, Wicha Max⁷, Hasan Korkaya³

¹Oncology, Wayne State University, Detroit, MI,²University of Michigan, Ann Arbor, MI,³Wayne State University, Detroit, MI,⁴Medical College of Georgia, Augusta, GA,⁵Institute of Immunology, Muenster, Germany,⁶Univ. of Michigan College of Pharmacy, Ann Arbor, MI,⁷Department of Internal Medicine, University of Michigan, Ann Arbor, MI

摘要 Abstract

中文摘要

三阴性乳腺癌（TNBC）以早期转移扩散和对免疫治疗反应不佳为特征，然而这种侵袭性行为背后的全身免疫机制仍未充分明确。我们采用整合了单细胞RNA测序（scRNA-seq）、高维质谱流式（CyTOF）、流式细胞分析、体内遗传扰动以及多种同源TNBC模型的综合多组学方法，初步数据提示，近期发现的一种中性粒细胞样单核细胞群体（NeuMo）选择性地在高转移肿瘤中出现。NeuMos表现出动态的单核-粒细胞转录谱，并启动由CXCL2和G-CSF信号驱动的促炎级联反应。该轴在脾脏中诱导强劲的应急性粒细胞生成，显著扩增出浸润肿瘤和外周组织的未成熟CD11b⁺Ly6G⁺CXCR2⁺粒细胞样细胞，从而建立全身性免疫抑制。相比之下，非转移性EMT6肿瘤维持着均衡的适应性和固有免疫区室，粒细胞活化极少，突显了NeuMo驱动的炎症对侵袭性TNBC状态的特异性。功能实验证明，删除该炎症回路的上游放大因子S100A9可破坏粒细胞扩增、减少脾肥大、降低肺转移，并在AT3和E0771 TNBC模型中显著增强PD-L1阻断的治疗疗效。这些发现将S100A9确立为免疫治疗耐药的关键介导因子。对包括TCGA在内的人类TNBC数据集的分析揭示，S100A8/A9、G-CSF和CXCL1/2基因程序的早期诱导与高级别肿瘤和不良生存相关，突显了该通路的临床相关性。总体而言，我们的研究将NeuMo驱动的炎症介导因子确定为连接TNBC肿瘤内在程序与全身免疫重塑、转移和检查点耐药的核心机制。这些结果不仅为侵袭性TNBC定义了一种新的基于髓系的生物标志物特征，也提名了S100A9/CXCL2/G-CSF轴作为改善免疫治疗结局的可干预治疗靶点。

查看英文原文 English abstract

Triple-negative breast cancer (TNBC) is characterized by early metastatic spread and poor response to immunotherapy, yet the systemic immune mechanisms underlying this aggressive behavior remain poorly defined. Using a comprehensive multi-omics approach that integrates single-cell RNA sequencing (scRNA-seq), high-dimensional mass cytometry (CyTOF), flow cytometry analyses, in vivo genetic perturbations, and multiple syngeneic TNBC models, our preliminary data suggested that recently introduced neutrophil-like monocyte population (NeuMo) emerges selectively within highly metastatic tumors. NeuMos exhibit a dynamic monocyte-granulocyte transcriptional profile and initiate a pro-inflammatory cascade driven by CXCL2, and G-CSF signaling. This axis induces robust emergency granulopoiesis in the spleen, markedly expanding immature CD11b⁺Ly6G⁺CXCR2⁺ granulocytic cells that infiltrate tumors and peripheral tissues establishing systemic immunosuppression. In contrast, non-metastatic EMT6 tumors maintain balanced adaptive and innate immune compartments with minimal granulocytic activation, highlighting the specificity of NeuMo-driven inflammation to aggressive TNBC states. Functional experiments demonstrate that deletion of S100A9, an upstream amplifier of this inflammatory circuit, disrupts granulocytic expansion, reduces splenic hypertrophy, diminishes lung metastasis, and significantly enhances the therapeutic efficacy of PD-L1 blockade in both AT3 and E0771 TNBC models. These findings put S100A9 as a critical mediator of immunotherapy resistance. Analysis of human TNBC datasets, including TCGA, reveals early induction of S100A8/A9, G-CSF, and CXCL1/2 gene programs associated with high-grade tumors and poor survival, underscoring the clinical relevance of this pathway. Collectively, our work identifies NeuMo-driven inflammatory mediator as a central mechanism linking TNBC tumor-intrinsic programs to systemic immune remodeling, metastasis, and checkpoint resistance. These results not only define a novel myeloid-based biomarker signature for aggressive TNBC but also nominate the S100A9/CXCL2/G-CSF axis as an actionable therapeutic target to improve immunotherapy outcomes.

利益披露 Disclosure

F. Alkan, None.. H. K. Alkan, None.. A. Caglayan, None.. A. Lawal, None.. N. Celiker, None.. T. Vogl, None.. W. Max, None.. H. Korkaya, None.

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