Efferocytosis and M2 Macrophage Polarization Gene Expression Correlates With Relapsed and Refractory Classical Hodgkin Lymphoma Patients: A Multi-Omic Analysis

IF 3.9 4区医学 Q2 HEMATOLOGY

Hematological Oncology Pub Date : 2025-09-21 DOI:10.1002/hon.70135

Juan Quarroz Braghini, María Cecilia Cabral Lorenzo, Laura Kornblihtt, Mariana S. De Lorenzo, Stella Maris Ranuncolo, Guillermo Blanco

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引用次数: 0

Abstract

Classical Hodgkin Lymphoma (cHL) exhibits rare malignant Hodgkin-Reed Sternberg (HRS) cells within a reactive immune microenvironment. This study developed an HRS cell gene expression signature to identify HRS cells in single-cell RNA sequencing (scRNA-seq) data, investigated cognate interactions, analyzed bulk transcriptomes, and assessed predictors of treatment failure. Differentially expressed genes (DEGs) from RelB-silenced U-HO1 cells were identified, and scRNA-seq data was processed to annotate cell types. Cognate interactions were analyzed using CellPhoneDB, and bulk transcriptome deconvolution was performed using CIBERSORT. Ridge regression models were built and evaluated. A 37-gene HRS cell signature identified HRS cells (2.7%) in scRNA-seq data, revealing efferocytosis pathway enrichment. Macrophages showed the highest cognate interactions, including efferocytosis-related interactions with HRS cells. Bulk transcriptome analysis of 130 cHL patients showed increased M2 macrophage proportions correlated with poorer treatment response (p < 0.001). Ridge regression predicted response to treatment (RtoT) with an AUC of 0.83, identifying HRS cells and M2 macrophages as key predictors. Hierarchical clustering based on 19 genes revealed distinct RtoT outcomes, with high efferocytosis/M2 gene expression correlating with poor response. Increased MerTK, CD209, CD14, and CD36 expression was associated with poorer outcomes. Combining gene expression and cell type proportions improved RtoT prediction (AUC 0.87). A validated HRS cell gene expression signature enabled precise HRS cell identification and accurate estimation of cell proportions. HRS cell and M2 macrophage proportions, along with efferocytosis-related genes, predicted treatment failure. Efferocytosis-mediated M2 macrophage polarization, controlled by HRS cells, may be a critical immune checkpoint in cHL.

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淋巴细胞增生和M2巨噬细胞极化基因表达与复发和难治性经典霍奇金淋巴瘤患者相关：多组学分析

经典霍奇金淋巴瘤（cHL）在反应性免疫微环境中表现出罕见的恶性霍奇金-里德斯特恩伯格（HRS）细胞。本研究开发了HRS细胞基因表达特征，以识别单细胞RNA测序（scRNA-seq）数据中的HRS细胞，研究同源相互作用，分析大量转录组，并评估治疗失败的预测因素。从relb沉默的U-HO1细胞中鉴定出差异表达基因（DEGs），并对scRNA-seq数据进行处理以注释细胞类型。使用CellPhoneDB分析同源相互作用，使用CIBERSORT进行大量转录组反褶积。建立岭回归模型并进行评价。在scRNA-seq数据中，37个基因的HRS细胞特征鉴定出HRS细胞（2.7%），揭示了efferocytosis途径的富集。巨噬细胞表现出最高的同源相互作用，包括与HRS细胞的efferocysis相关的相互作用。130例cHL患者的大量转录组分析显示，M2巨噬细胞比例增加与较差的治疗反应相关（p < 0.001）。Ridge回归预测治疗反应（RtoT）的AUC为0.83，确定HRS细胞和M2巨噬细胞为关键预测因子。基于19个基因的分层聚类揭示了不同的RtoT结果，高efferocytosis/M2基因表达与不良反应相关。MerTK、CD209、CD14和CD36表达增加与预后较差相关。结合基因表达和细胞类型比例可改善RtoT预测（AUC 0.87）。经过验证的HRS细胞基因表达签名能够精确地识别HRS细胞并准确估计细胞比例。HRS细胞和M2巨噬细胞比例，以及efferocysis相关基因，预测治疗失败。由HRS细胞控制的efferocyth介导的M2巨噬细胞极化可能是cHL的一个关键免疫检查点。

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来源期刊

Hematological Oncology 医学-血液学

CiteScore

4.20

自引率

6.10%

发文量

147

审稿时长

>12 weeks

期刊介绍： Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged: -Clinical practice and management of hematological neoplasia, including: acute and chronic leukemias, malignant lymphomas, myeloproliferative disorders -Diagnostic investigations, including imaging and laboratory assays -Epidemiology, pathology and pathobiology of hematological neoplasia of hematological diseases -Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies -Aspects of the cell biology, molecular biology, molecular genetics and cytogenetics of normal or diseased hematopoeisis and lymphopoiesis, including stem cells and cytokines and other regulatory systems. Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.