PO.TB10.11 · 肿瘤生物学
非免疫基质重编程塑造乳腺癌免疫治疗耐药：来自小鼠模型的启示
Non-immune stromal reprogramming shapes breast cancer immunotherapy resistance: insights from mouse models
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：PD-1/PD-L1 阻断仅使一部分乳腺癌患者获益。尽管肿瘤细胞和免疫细胞已被广泛研究，但非免疫基质（如内皮细胞（ECs）和癌症相关成纤维细胞（CAFs））在治疗耐药中的作用仍知之甚少。
方法：我们对三种 ICB 反应存在差异的同基因乳腺癌模型（4T1：耐药；EMT6：部分应答；EO771：应答）的 CD45⁻ 细胞进行了单细胞 RNA 测序。我们分析了基质组成、功能程序（GO 生物学过程）以及肿瘤-基质旁分泌通讯（CellChat）。并将研究结果与已发表的人类乳腺癌和肺癌数据集（Cell Res 30, 745-762 (2020)）进行了比较。
结果：不同的基质状态与 ICB 结局相关。4T1 富集以成纤维细胞和细胞外基质为主的基质，并伴有免疫沉默的内皮；而 EMT6 肿瘤则表现出内皮扩增和干扰素活跃的 CAFs。EO771 肿瘤呈现由周细胞稳定的静止血管系统以及免疫刺激性成纤维细胞程序。通路水平分析突显了基质通讯的保守模式，并鉴定出与人类队列中疾病分期相关的成纤维细胞相关特征。通路水平分析突显了基质通讯的保守模式，并鉴定出与人类队列中疾病分期相关的成纤维细胞相关特征。
结论：基质重编程促成了 ICB 耐药。跨物种分析突显内皮细胞和成纤维细胞状态可作为潜在的生物标志物和治疗切入点，以增强免疫治疗疗效。
查看英文原文 English abstract
Background: PD-1/PD-L1 blockade benefits only a subset of breast cancer patients.While tumor and immune cells have been extensively studied, the role of non-immunestroma such as endothelial cells (ECs) and cancer-associated fibroblasts (CAFs) intherapeutic resistance is less understood.
Methods: We performed single-cell RNA sequencing of CD45⁻ cells from threesyngeneic breast cancer models with divergent ICB responses (4T1: resistant, EMT6:partial responder, EO771: responder). Stromal composition, functional programs (GOBiological Process), and tumor-stroma paracrine communication (CellChat) wereanalyzed. Findings were compared with published human breast and lung cancerdatasets (Cell Res 30, 745-762 (2020)).
Results: Distinct stromal states were linked to ICB outcomes. 4T1 were enriched forfibroblast- and extracellular matrix-dominant stroma with immune-silent endothelium,while EMT6 tumors showed endothelial expansion and interferon-active CAFs. EO771tumors displayed pericyte-stabilized, quiescent vasculature and immune-stimulatoryfibroblast programs. Pathway-level analysis highlighted conserved modes of stromalcommunication and identified fibroblast-associated signatures that correlated withdisease stage in human cohorts. Pathway-level analysis highlighted conserved modesof stromal communication and identified fibroblast-associated signatures that correlatedwith disease stage in human cohorts.
Conclusions: Stromal reprogramming contributes to ICB resistance. Cross-speciesanalysis highlights endothelial and fibroblast states as potential biomarkers andtherapeutic entry points to enhance immunotherapy efficacy.
利益披露 Disclosure
Y. Yue,
Genentech Employment.
S. Mittman,
Genentech Employment.
R. Reja,
Genentech Employment.
J. Lau,
Genentech Employment.
M. Shi,
Genentech Employment.
A. Xavier-Magalhaes,
Genentech Employment.
J. Paw,
Genentech Employment.
C. De Amat Herbozo,
Genentech Employment.
M. De Simone,
Genentech Employment.
Y. Qu,
Genentech Employment.