Dai Liyuan, Lou Ning, Huang Liling, Li Lin, Tang Le, Shi Yuankai, Han Xiaohong
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
Clinical Pharmacology Research Center, Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK & PD Investigation for Innovative Drugs, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1, Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
Cancer Immunol Immunother. 2025 Feb 25;74(4):123. doi: 10.1007/s00262-025-03968-7.
Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous malignancy with diverse patient outcomes, largely influenced by the tumor microenvironment (TME). Understanding the roles of fibroblasts and macrophages within the TME is essential for developing personalized therapeutic strategies in DLBCL.
This study is a multi-omics approach, integrating spatial transcriptomics (n = 11), bulk transcriptomics (n = 2,499), immunohistochemistry (IHC, n = 37), multiplex immunofluorescence (mIF, n = 56), and plasma samples (n = 240) to identify and characterize fibroblast and tumor-associated macrophage subtypes in the TME. Hub genes for LYZ fibroblasts and FN1 macrophages were selected through univariate Cox regression and random forest analyses. Their prognostic significance was validated using IHC, mIF, and autoantibody assays in DLBCL patients treated with R-CHOP and in non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs).
Fibroblasts and macrophages were classified into two distinct subtypes. Patients with higher LYZ fibroblasts infiltration demonstrated superior prognosis, which was associated with increased infiltration of FN1 macrophages. Key hub genes identified for LYZ fibroblasts included LYZ, ANPEP, CSF3R, C15orf48, LILRB4, CLEC7A, and COL7A1, while hub FN1 macrophages genes included COL1A1, FN1, APOE, DCN, MMP2, SPP1, COL3A1, and COL1A2. Independent prognostic markers in DLBCL treated with R-CHOP and NSCLC treated with ICIs were identified, including LYZ and LILRB4 at both protein and mRNA levels, and COL1A2 autoantibodies (p < 0.05). In DLBCL patients treated with R-CHOP, FN1 mRNA and autoantibody levels were also prognostic markers (p < 0.05). In NSCLC treated with ICIs, COL3A1 autoantibody was prognostic marker (p < 0.05).
This study identified a prognostically relevant LYZ fibroblasts and FN1 macrophages in DLBCL. The hub genes associated with these subtypes represent potential biomarkers, providing insights into improving patient outcomes in DLBCL.
弥漫性大B细胞淋巴瘤（DLBCL）是一种临床异质性恶性肿瘤，患者预后各异，很大程度上受肿瘤微环境（TME）影响。了解TME中成纤维细胞和巨噬细胞的作用对于制定DLBCL的个性化治疗策略至关重要。
本研究采用多组学方法，整合空间转录组学（n = 11）、批量转录组学（n = 2499）、免疫组织化学（IHC，n = 37）、多重免疫荧光（mIF，n = 56）和血浆样本（n = 240），以识别和表征TME中的成纤维细胞和肿瘤相关巨噬细胞亚型。通过单变量Cox回归和随机森林分析选择LYZ成纤维细胞和FN1巨噬细胞的枢纽基因。使用IHC、mIF和自身抗体检测在接受R-CHOP治疗的DLBCL患者和接受免疫检查点抑制剂（ICI）治疗的非小细胞肺癌（NSCLC）患者中验证其预后意义。
成纤维细胞和巨噬细胞分为两种不同的亚型。LYZ成纤维细胞浸润较高的患者预后较好，这与FN1巨噬细胞浸润增加有关。为LYZ成纤维细胞鉴定的关键枢纽基因包括LYZ、ANPEP、CSF3R、C15orf48、LILRB4、CLEC7A和COL7A1，而枢纽FN1巨噬细胞基因包括COL1A1、FN1、APOE、DCN、MMP2、SPP1、COL3A1和COL1A2。确定了接受R-CHOP治疗的DLBCL和接受ICI治疗的NSCLC中的独立预后标志物，包括蛋白质和mRNA水平的LYZ和LILRB4，以及COL1A2自身抗体（p < 0.05）。在接受R-CHOP治疗的DLBCL患者中，FN1 mRNA和自身抗体水平也是预后标志物（p < 0.05）。在接受ICI治疗的NSCLC中，COL3A1自身抗体是预后标志物（p < 0.05）。
本研究在DLBCL中鉴定出与预后相关的LYZ成纤维细胞和FN1巨噬细胞。与这些亚型相关的枢纽基因代表潜在的生物标志物，为改善DLBCL患者的预后提供了见解。
