PO.TB10.09 · 肿瘤生物学

单细胞图谱揭示不同的免疫串扰轴定义NSCLC中不同EGFR突变状态的肿瘤微环境

Distinct immune crosstalk axes define the tumor microenvironment across EGFR mutation status in NSCLC by single-cell profiling

编号 7388 展板 5 时间 4/22 09:00–12:00 区域 Section 27 主讲 Yoojin Kim, BA

分会场 Functional and Spatial Regulation of Immune Evasion and Anti-Tumor Immunity

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作者与单位 Authors & Affiliations

Yoojin Kim¹, Hyunsu Kim², Kyungjong Lee³, Bo Mi Ku², Hae-Ock Lee⁴, Jinyong Kim², Hyun Ae Jung², Jong-Mu Sun², Se-Hoon Lee², Jin Seok Ahn², Myung-Ju Ahn², Sehhoon Park²

¹Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea, Republic of,²Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of,³Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of,⁴Department of Biomedicine and Health Sciences, Graduate School, The Catholic University of Korea, Seoul, Korea, Republic of

摘要 Abstract

中文摘要

背景：表皮生长因子受体（EGFR）是非小细胞肺癌（NSCLC）的主要致癌驱动因子。如先前报道，与EGFR野生型肿瘤患者相比，EGFR突变型NSCLC患者对免疫检查点抑制剂（ICI）的响应有限。EGFR突变型NSCLC中原发性ICI耐药的机制及其独特的肿瘤微环境（TME）特征仍知之甚少。方法：我们对来自88例患者（31例EGFR突变型，57例EGFR野生型）的初治NSCLC样本进行了单细胞RNA测序，以表征TME。数据处理、标准化、降维和聚类使用Seurat软件包进行。细胞类型用经典标志基因注释，过渡性上皮细胞群体进一步通过共识非负矩阵分解（cNMF）鉴定。通过计算推断细胞间通讯网络，并通过差异表达和通路富集分析支持所鉴定的相互作用。结果：通过分析241,333个高质量单细胞，我们鉴定出33,628个上皮细胞。cNMF基于干扰素驱动的免疫程序揭示了一个炎症性过渡上皮（Epi_inflammatory）亚群。在EGFR野生型肿瘤中，这些Epi_inflammatory细胞通过MHC I类-CD8信号与CD8+组织驻留记忆T（Trm）细胞表现出主导性相互作用。上皮细胞表现出更高的关键抗原呈递基因（B2M、TAP1、PSMB8/9）表达，而CD8+ Trm细胞则表现出细胞毒性标志物（GZMB、PRF1、NKG7）表达升高以及差异表达的TCR库相关基因，表明T细胞活化增强。GSEA显示CD8+ Trm细胞中"细胞杀伤"通路富集，以及上皮细胞中"内源性肽抗原的抗原加工与呈递"富集，支持EGFR野生型肿瘤中主导性的MHC I类介导的相互作用。相反，在EGFR突变型肿瘤中推断出肿瘤相关巨噬细胞（TAM）与CD8+ Trm细胞之间的串扰增强，主要由SPP1-CD44配体-受体轴驱动。缺氧型和STAB1+ TAM表现出SPP1水平上调和抗原呈递基因表达降低，而CD8+ Trm细胞则表达更高的CD44水平。值得注意的是，巨噬细胞中SPP1的表达与CD8+ Trm细胞的耗竭评分呈正相关（p = 0.041）。结论：我们的发现提示存在不同的免疫图景；EGFR突变型肿瘤通过SPP1-CD44轴表现出巨噬细胞驱动的免疫抑制性TME，导致CD8+ Trm功能障碍，而EGFR野生型肿瘤则表现出上皮-CD8+ Trm串扰，建立了细胞毒性微龛。这种差异可能解释了ICI治疗在EGFR突变型NSCLC中获益有限的原因。

查看英文原文 English abstract

Background : Epidermal growth factor receptor (EGFR) is a major oncogenic driver in non-small cell lung cancer (NSCLC). Patients with EGFR-mutant NSCLC show limited responses to immune checkpoint inhibitors (ICIs) compared with those with EGFR-wild-type tumors, as previously reported. The mechanisms underlying primary ICI resistance and distinct tumor microenvironment (TME) characteristics in EGFR-mutant NSCLC remain poorly understood. Methods : We performed single-cell RNA sequencing of treatment-naïve NSCLC samples from 88 patients (31 EGFR-mutant, 57 EGFR-wild-type) to characterize TME. Data processing, normalization, dimensional reduction, and clustering were conducted with Seurat package. Cell types were annotated with canonical marker genes, and transitional epithelial populations were further identified through consensus non-negative matrix factorization (cNMF). Cell-cell communication networks were computationally inferred , and the identified interactions were supported through differential expression and pathway enrichment analyses. Results : By profiling 241,333 high-quality single cells, we identified 33,628 epithelial cells. cNMF revealed an inflammatory transitional epithelial (Epi_inflammatory) subset based on interferon-driven immune programs. In EGFR-wild-type tumors, these Epi_inflammatory cells showed dominant interactions with CD8+ tissue-resident memory T (Trm) cells through MHC class I-CD8 signaling. The epithelial cells exhibited higher expression of key antigen-presentation genes ( B2M, TAP1, PSMB8/9 ), while CD8+ Trm cells showed elevated expression of cytotoxic markers ( GZMB, PRF1, NKG7 ) and differentially expressed TCR repertoire-associated genes, indicating enhanced T-cell activation. GSEA showed enrichment of the “ Cell killing ” pathway in CD8+ Trm cells and “ Antigen processing and presentation of endogenous peptide antigen ” in epithelial cells, supporting dominant MHC class I-mediated interaction in EGFR-wild-type tumors. In contrast, intensified crosstalk between tumor-associated macrophages (TAMs) and CD8+ Trm cells was inferred in EGFR-mutant tumors, predominantly driven by the SPP1-CD44 ligand-receptor axis. Hypoxic and STAB1+ TAMs displayed upregulated SPP1 levels and reduced antigen-presentation genes expression, while CD8+ Trm cells expressed higher CD44 levels. Notably, expression of SPP1 in macrophages positively correlated with the exhaustion score of CD8+ Trm cells (p = 0.041). Conclusion : Our findings suggest distinct immune landscapes; EGFR-mutant tumors showed macrophage-driven immunosuppressive TME via SPP1-CD44 axis, leading to CD8+ Trm dysfunction, whereas EGFR-wild-type tumors exhibited epithelial-CD8+ Trm crosstalk, establishing a cytotoxic niche. This divergence may explain the limited benefit of ICI therapy in EGFR-mutant NSCLC.

利益披露 Disclosure

Y. Kim, None.. H. Kim, None.. K. Lee, None.. B. Ku, None.. H. Lee, None.. J. Kim, None.. H. Jung, None.. J. Sun, None.. S. Lee, None.. J. Ahn, None.. M. Ahn, None.. S. Park, None.

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