PO.TB10.05 · 肿瘤生物学

单细胞RNA测序揭示非小细胞肺癌中与祖源相关的分子和细胞免疫抑制特征

Single-cell RNA sequencing reveals ancestry-associated molecular and cellular immunosuppressive features in non-small cell lung cancer

编号 2092 展板 22 时间 4/20 09:00–12:00 区域 Section 26 主讲 Pengbo Zhang, BS;MS

分会场 Aging and Host Determinants of Tumor Progression: The Macroenvironmental Axis

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作者与单位 Authors & Affiliations

Liang Liu¹, Pengbo Zhang², Enzo Palma¹, Ashley Ballard¹, Lance Miller¹, Gregory Hawkins³, Cristina M. Furdui³, Edward Levine⁴, Alberto de Hoyos⁵, Wencheng Li⁶, Fang-Chi Hsu⁷, Ralph D'Agostino⁷, David Foureau⁸, Wei Zhang¹

¹Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC,²Atrium Wake Forest Baptist Comprehensive Cancer Center, Winston Salem, NC,³Biochemistry, Wake Forest University School of Medicine, Winston Salem, NC,⁴General Surgery, Wake Forest University School of Medicine, Winston Salem, NC,⁵Cardiothoracic Surgery, Wake Forest University School of Medicine, Winston Salem, NC,⁶Pathology, Wake Forest University School of Medicine, Winston Salem, NC,⁷Biostatistics and Data Science, Wake Forest University School of Medicine, Winston Salem, NC,⁸Cancer Medicine, Wake Forest University School of Medicine, Winston Salem, NC

摘要 Abstract

中文摘要

背景：非小细胞肺癌（NSCLC）结局中的种族差异持续存在，非裔美国人（BA）患者相较于白人美国人（WA）患者生存较差，即使在校正分期、治疗和社会经济因素后仍是如此。我们假设肿瘤微环境（TME）中独特的分子和细胞特征促成了祖源特异性的异质性和这些差异。方法：我们对来自42例患者的初治、早期NSCLC进行了10x scRNA-seq：29例腺癌（15例WA，14例BA）和13例鳞癌（10例WA，3例BA）。对220,591个细胞进行无监督聚类和注释，鉴定出六种主要细胞类型：上皮细胞、内皮细胞、成纤维细胞、髓系细胞、肥大细胞和淋巴细胞——每种进一步细分为谱系特异性表型。按祖源分层的分析包括：差异基因表达和细胞丰度、基因集富集分析、轨迹推断和配体-受体分析。结果：恶性上皮细胞在BA肿瘤中显示OXPHOS、脂肪酸代谢和G2/M检查点的显著通路富集（q≤0.01），而在WA肿瘤中显示经NF-κB的TNF-alpha信号传导、IFN-gamma应答和血红素代谢（q分别为0.004、0.008和0.02）。内皮细胞在BA肿瘤中富集IL-2/STAT5信号传导和脂肪酸代谢（q分别为0.01和0.03），在WA肿瘤中富集增殖通路（Myc Targets V1，q=0.005）。BA和WA肿瘤表现出不同的免疫抑制特征。BA肿瘤显示更高数量的FAP-癌症相关成纤维细胞（CAF；q=0.07）和M2巨噬细胞（q=0.004），但效应CD8+（p=0.02）和gammadelta T细胞（p=0.018）较低。BA肿瘤相关巨噬细胞（TAM）显示活化保留（CD40、CD80），但抗原呈递受损（HLA-DM/DQ/DR，q均<0.05），并富集缺氧和TGF-beta信号传导基因特征（q<0.01）。相反，WA肿瘤含有更多FAP+ CAF，且巨噬细胞表现出M0/M1样特征，具有显著的抗原呈递和IFN-I/II应答（q<0.01）。此外，BA肿瘤显示活跃的固有免疫网络，尤其是SPP1-CD44信号传导（p<0.001），而WA肿瘤表现出更强的适应性刺激（MHCII-TCR）和抑制性（CD86-CTLA4）信号传导（p<0.001）。此外，BA肿瘤中的CD8⁺ T细胞采取了与TGF-beta信号传导相关的早期耗竭表型（q<0.01），而WA肿瘤中它们在IFN-alpha/gamma驱动的环境中显示进行性耗竭（高PDCD1、HAVCR2、LAG3）（q<1E-5）。结论：这个首个大规模、按祖源分层的NSCLC scRNA-seq图谱揭示了BA和WA患者中独特免疫抑制程序背后的分子机制，并突显了可能促成NSCLC种族差异的分子和细胞TME特征。

查看英文原文 English abstract

Background: Racial disparities in non-small cell lung cancer (NSCLC) outcomes persist, with Black American (BA) patients having inferior survival compared to White American (WA) patients, even after adjusting for stage, treatment, and socioeconomic factors. We hypothesize that distinct molecular and cellular features in the tumor microenvironment (TME) contribute to ancestry-specific heterogeneity and these disparities. Methods: We performed 10x scRNA-seq on treatment-naïve, early-stage NSCLC from 42 patients: 29 adenocarcinomas (15 WA, 14 BA) and 13 squamous (10 WA, 3 BA). Unsupervised clustering and annotation of 220,591 cells identified six major cell types: epithelial, endothelial, fibroblasts, myeloid, mast, and lymphocytes-each further subdivided into lineage-specific phenotypes. Analyses stratified by ancestry include: differential gene expression and cell abundance, gene set enrichment analysis, trajectory inference, and ligand-receptor analysis. Results: Malignant epithelial cells showed significant pathway enrichment of OXPHOS, fatty acid metabolism, and G2/M checkpoint in BA tumors (q≤0.01) and TNF-alpha signaling via NF-κB, IFN-gamma response, and heme metabolism in WA tumors (q=0.004, 0.008, and 0.02, respectively). Endothelial cells showed enrichment in IL-2/STAT5 signaling and fatty acid metabolism in BA tumors (q=0.01 and 0.03, respectively) and in proliferation pathways in WA tumors (Myc Targets V1, q=0.005).BA and WA tumors exhibited distinctive immunosuppressive features. BA tumors showed higher numbers of FAP- cancer associated fibroblasts (CAF; q=0.07) and M2 macrophages (q=0.004) but low effector CD8+ (p=0.02) and gammadelta T cells (p=0.018). BA tumor associated macrophages (TAM) showed preserved activation (CD40, CD80) but impaired antigen presentation (HLA-DM/DQ/DR, all q<0.05) and were enriched for hypoxia and TGF-beta signaling gene signatures (q<0.01). In contrast, WA tumors contained more FAP+ CAFs and macrophages displayed M0/M1-like features with prominent antigen presentation and IFN-I/II responses (q<0.01). Also, BA tumors showed active innate immune networks, particularly SPP1-CD44 signaling (p<0.001), whereas WA tumors exhibited stronger adaptive stimulatory (MHCII-TCR) and inhibitory (CD86-CTLA4) signaling (p<0.001). Furthermore, CD8⁺ T cells in BA tumors adopted an early exhaustion phenotype associated with TGF-beta signaling (q<0.01), while in WA tumors they showed progressive exhaustion (high PDCD1, HAVCR2, LAG3) in an IFN-alpha/gamma-driven environment (q<1E-5). Conclusions: This first large-scale, ancestry-stratified scRNA-seq atlas of NSCLC reveals molecular mechanisms underlying distinctive immunosuppressive programs in BA and WA patients and highlights molecular and cellular TME features that may contribute to racial disparities in NSCLC.

利益披露 Disclosure

L. Liu, None.. P. Zhang, None.. E. Palma, None.. A. Ballard, None.. L. Miller, None.. G. Hawkins, None.. C. M. Furdui, None.. E. Levine, None.. A. de Hoyos, None.. W. Li, None.. F. Hsu, None.. R. D'Agostino, None.. D. Foureau, None.. W. Zhang, None.

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