PO.CL05.10 · 临床研究
靶向OSM-OSMR信号轴以重编程肿瘤微环境并克服胰腺癌中的免疫抑制
Targeting the OSM-OSMR signaling axis to reprogram the tumor microenvironment and overcome immune suppression in pancreatic cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胰腺导管腺癌（PDA）是最致命的恶性肿瘤之一，其特征是致密的、纤维化的、免疫排斥的肿瘤微环境（TME），对当前疗法耐药。新出现的证据表明，抑瘤素M（OSM）-抑瘤素M受体（OSMR）信号轴（IL-6细胞因子家族的成员）通过调控肿瘤-基质-免疫相互作用，是PDA进展的关键驱动因素。我的研究旨在阐明OSM-OSMR信号如何协调PDA中的免疫抑制性微环境，并评估其抑制是否能将肿瘤重编程为对免疫有应答的状态。对未经治疗的人PDA进行空间转录组学分析发现，高OSMR表达与癌症相关成纤维细胞（CAF）激活、基质硬度以及巨噬细胞和单核细胞基因特征的富集相关，同时CD8+ T细胞浸润减少。整合转录组学分析鉴定出富集于NF-kB、JAK-STAT和IFN-gamma通路的OSMR相关基因。功能研究显示，OSM-OSMR信号促进PDA细胞增殖、迁移和侵袭，同时驱动CAF激活和单核细胞向免疫抑制性CD163+/CD206+巨噬细胞极化。在离体人PDA切片培养中，重组OSM增强了增殖和STAT3磷酸化，这些效应可被OSM或OSMR中和抗体逆转。为剖析其潜在机制，我采用了CRISPR工程化的OSMR敲除和回复PDA细胞系、OSMR过表达的CAF，以及与单核细胞来源巨噬细胞的3D共培养，并整合单细胞RNA测序、磷酸化蛋白质组学和空间转录组学。平行的转化研究将在患者来源类器官、肿瘤切片培养和基因工程小鼠模型（GEMM）中，单独或与FDA批准的化疗联合，检测OSM/OSMR中和抗体。这些研究将评估OSM-OSMR信号对肿瘤生长、基质重塑、免疫浸润和转移的影响。通过阐明OSM-OSMR信号如何维持PDA的纤维化和免疫抑制性TME并确立其治疗弱点，本工作旨在开发合理策略，重编程TME、增强免疫治疗应答，并改善胰腺癌患者的预后。
查看英文原文 English abstract
Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest malignancies, characterized by a dense, fibrotic, and immune‑excluded tumor microenvironment (TME) that resists current therapies. Emerging evidence implicates the Oncostatin M (OSM)-Oncostatin M receptor (OSMR) signaling axis, a member of the IL‑6 cytokine family, as a key driver of PDA progression through regulation of tumor-stroma-immune interactions. My research aims to define how OSM-OSMR signaling orchestrates the immune‑suppressive microenvironment in PDA and to evaluate whether its inhibition can reprogram tumors toward immune responsiveness.Spatial transcriptomics analysis of treatment‑naïve human PDA revealed high OSMR expression associated with cancer‑associated fibroblast (CAF) activation, stromal stiffness, and enrichment of macrophage and monocyte gene signatures, alongside reduced CD8⁺ T‑cell infiltration. Integrated transcriptomic analyses identified OSMR‑associated genes enriched for NF‑κB, JAK-STAT, and IFN‑gamma pathways. Functional studies showed that OSM-OSMR signaling promotes PDA cell proliferation, migration, and invasion, while driving CAF activation and polarization of monocytes toward immunosuppressive CD163⁺/CD206⁺ macrophages. In ex vivo human PDA slice cultures, recombinant OSM enhanced proliferation and STAT3 phosphorylation, effects reversed by OSM or OSMR neutralizing antibodies.To dissect the underlying mechanisms, I employed CRISPR‑engineered OSMR knockout and rescue PDA cell lines, OSMR‑overexpressing CAFs, and 3D co‑cultures with monocyte‑derived macrophages, integrated with single‑cell RNA‑seq, phospho‑proteomics, and spatial transcriptomics. Parallel translational studies will test OSM/OSMR‑neutralizing antibodies in patient‑derived organoids, tumor slice cultures, and genetically engineered mouse models (GEMMs), alone or in combination with FDA‑approved chemotherapies. These studies will assess the effects of OSM-OSMR signaling on tumor growth, stromal remodeling, immune infiltration, and metastasis.By defining how OSM-OSMR signaling sustains PDA's fibrotic and immune‑suppressive TME and establishing its therapeutic vulnerability, this work aims to develop rational strategies that reprogram the TME, enhance immunotherapy responsiveness, and improve outcomes for patients with pancreatic cancer.
利益披露 Disclosure
Y. Sui, None.