PO.TB10.03 · 肿瘤生物学
空间转录组分析揭示与肺腺癌免疫检查点阻断反应相关的独特肿瘤微环境重塑模式
Spatial transcriptomic profiling reveals distinct tumor microenvironment remodeling patterns associated with immune checkpoint blockade response in lung adenocarcinoma
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摘要 Abstract
中文摘要
尽管免疫检查点阻断（ICB）改善了非小细胞肺癌（NSCLC）的临床结局，许多患者仍存在耐药，突显了理解肿瘤微环境（TME）在治疗期间如何演变的必要性。因此，本研究旨在表征与ICB相关的空间TME重塑。我们对来自七例肺腺癌患者的配对治疗前后肿瘤样本进行了10x Genomics Visium空间转录组分析。根据实体瘤免疫疗效评价标准，三例患者被归类为反应者（均为疾病稳定），并与四例无反应者进行比较。反应者组平均接受13个ICB周期，而无反应者接受2个周期。治疗前样本取自肺（n = 4）和淋巴结（n = 3），而治疗后样本采集自肺（n = 2）、淋巴结（n = 2）、骨（n = 2）和脑（n = 1）。质量控制后，平均斑点数为2212，最少266个斑点，最多4715个斑点，共计30,968个斑点。空间分析表明，反应者在治疗前和治疗后样本中均表现出更高的浆细胞和B细胞浸润。相比之下，无反应者在两个时间点均显示癌症相关成纤维细胞（CAF）比例增加。在治疗前样本中，反应者显示HLA-DMA和HLA-C上调，提示抗原呈递通路得以保留。此外，IGKC、IGHG2和IGHG1上调，表明B细胞活化。无反应者显示细胞外基质（ECM）重塑基因（TMSB4X、ACTB）和铁蛋白代谢基因（FTL）上调。在治疗后样本中，无反应者还显示ECM重塑基因（COL5A1、COL5A2、COL6A2、COL6A1、FN1、TIMP2、MMP2、MMP14）上调，表明肿瘤细胞对恶劣微环境的适应增强，并与M2样巨噬细胞极化存在潜在联系。总之，我们的发现表明，ICB反应者表现出浆细胞/B细胞富集的TME，而无反应者以CAF浸润增加以及ECM重塑和铁蛋白代谢基因上调为特征，提示了一种潜在的免疫耐药机制。我们目前正在一个独立队列中验证这种铁蛋白相关ECM重塑特征对ICB治疗结局的影响。
查看英文原文 English abstract
Although immune checkpoint blockade (ICB) has improved clinical outcomes in non-small cell lung cancer (NSCLC), many patients remain resistant, underscoring the need to understand how the tumor microenvironment (TME) evolves during therapy. Therefore, this study aims to characterize spatial TME remodeling associated with ICB. We performed 10x Genomics Visium spatial transcriptomic profiling on paired pre- and post-treatment tumor samples from seven patients with lung adenocarcinoma. Three patients were classified as responders based on immune Response Evaluation Criteria In Solid Tumors criteria (all stable disease) and were compared with four non-responders. The responder group received a mean of 13 ICB cycles, whereas non-responders received 2 cycles. Pre-treatment samples were obtained from lung (n = 4) and lymph node (n = 3), while post-treatment samples were collected from lung (n = 2), lymph node (n = 2), bone (n = 2), and brain (n = 1). After quality control, the mean number of spots was 2212, with a minimum of 266 spots, a maximum of 4715 spots, for a total of 30,968 spots. Spatial profiling demonstrated that responders exhibited consistently higher infiltration of plasma cells and B cells in both pre- and post-treatment samples. In contrast, non-responders showed increased proportions of cancer-associated fibroblasts (CAFs) at both time points. In the pre-treatment samples, responders showed upregulation of HLA-DMA and HLA-C, suggesting preservation of antigen presentation pathways. Additionally, IGKC, IGHG2, and IGHG1 were upregulated, indicating B-cell activation. Non-responders showed upregulation of extracellular matrix (ECM)-remodeling genes (TMSB4X, ACTB) and ferritin metabolism genes (FTL). In the post-treatment samples, non-responders also showed upregulation of ECM-remodeling genes (COL5A1, COL5A2, COL6A2, COL6A1, FN1, TIMP2, MMP2, MMP14), indicating enhanced tumor cell adaptation to a hostile microenvironment and a potential link to M2-like macrophage polarization. In summary, our findings demonstrate that ICB responders exhibit plasma/B-cell-enriched TMEs, whereas non-responders are characterized by increased CAF infiltration along with ECM remodeling and ferritin metabolism gene upregulation, suggesting a potential mechanism of immune resistance. We are currently validating the impact of this ferritin-associated ECM remodeling signature on ICB therapy outcomes in an independent cohort.
利益披露 Disclosure
H. Yoon, None..
J. Choi, None..
S. Lee, None..
J. Chung, None..
H. Kim, None.