PO.CL05.10 · 临床研究

从诊断到RCHOP复发的纵向弥漫性大B细胞淋巴瘤（DLBCL）病例中肿瘤免疫微环境（TME）的动态变化

Tumor immune micro-environment (TME) dynamics in longitudinal diffuse large B-cell lymphoma (DLBCL) cases from diagnosis to RCHOP relapse

编号 7944 展板 19 时间 4/22 09:00–12:00 区域 Section 49 主讲 Raoul Santiago, MD

分会场 Tumor Microenvironment Modulators

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作者与单位 Authors & Affiliations

Raoul Santiago¹, Raquel Aloyz², Stéphanie Bianco¹, Svetlana Dmitrienko², Nathalie Johnson², Andreas I. Papadakis³, Naciba Benlimame⁴, Cynthia Guilbert², Alan Spatz⁵, François E. Mercier², Madelyne Abraham², Laura Hilton⁶, David W. Scott⁶, Koren K. Mann⁷, Sarit Assouline²

¹Research Center, CHU of Quebec, Laval University, Quebec, QC, Canada,²Segal Cancer Centre and Lady Davis Institute for Medical Research, Montreal, QC, Canada,³Molecular pathology, Lady Davis Institute for Medical Research, Montreal, QC, Canada,⁴The George and Olga Minarik Research Pathology Facility, Lady Davis Institute for Medical Research, Montreal, QC, Canada,⁵Molecular pathology, Lady Davis Institute for Medical Research, Montreal, QC, Canada, Montreal, QC, Canada,⁶Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada,⁷Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada

摘要 Abstract

中文摘要

来自单核分析的DLBCL基因表达特征最近鉴定出了新的肿瘤微环境（TME）原型（LymphoMAPs），这些原型与RCHOP和CAR-T细胞敏感性相关。虽然某些原型在诊断或复发时富集，但其在疾病进展过程中的稳定性仍不清楚。我们使用LymphoMAP特征和组织学注释分析了纵向DLBCL病例，以评估RCHOP后的原型转换。方法：我们利用了两个独立的、注释完善的DLBCL队列，配对了诊断/复发活检：23例内部病例（46份样本）和44例已发表病例（88份样本）。我们队列中的基因表达使用NanoString癌症免疫Panel在固定（FFPE）标本上进行分析。外部数据集包括来自FFPE或新鲜冷冻样本、RCHOP前后的全转录组数据。LymphoMapR从归一化计数中预测原型：富含成纤维细胞和肿瘤相关巨噬细胞（FMAC）、初始和记忆T细胞（LN）、活化巨噬细胞和耗竭T细胞（TEX）。分类概率<0.7的样本被排除。此外，我们将原型与我们队列的组织学注释进行了相关分析。免疫组化（IHC）支持T细胞标志物（CD3、CD4、CD8）和PDL1表达。多重OPAL成像对巨噬细胞标志物（CD68、CD163）连同免疫检查点（CD47），以及趋化因子（CXCL9和CXCL10）连同受体（CXCR3）进行了定量。结果：在内部队列中，8例患者仅接受RCHOP后复发，其余接受了≥1种复发治疗方案。每个队列各有1例患者因LymphoMAP置信度低被排除。值得注意的是，原型转换发生在内部队列22例患者中的13例（59%，95% CI：36-79%）和外部队列43例患者中的18例（42%，95% CI：28-57%）。为提高统计效力，将两个队列合并，得出总体转换率为48%（95% CI：36-60%）。对于诊断时为LN的患者，转换频率（38%，95% CI：23-57%）低于FMAC（59%，95% CI：36-78%）或TEX（57%，95% CI：33-79%），但未观察到一致的转换方向或与复发时间的相关性。生发中心B细胞样（GCB）DLBCL主要为LN原型（58%），而非GCB则涵盖所有LymphoMAP原型，提示与起源细胞相关。组织学与LymphoMAP预测一致：T细胞丰度（CD3、CD4、CD8）和CXCR3表达在TEX中最高，其次是LN和FMAC（p<0.05）。IHC还显示，与诊断时相比，复发时CD3和CD8 T细胞显著减少。结论：根据我们的观察，DLBCL的免疫环境是动态的。尽管复发样本表现出更为T细胞耗竭的环境，但TME原型的变化频繁发生，且无占主导的模式。在为CAR-T细胞治疗选择患者的背景下，不应根据诊断时的TME推断复发时的TME。

查看英文原文 English abstract

DLBCL gene expression signatures from single-nucleus analyses have recently identified new tumor microenvironment (TME) archetypes (LymphoMAPs) linked to RCHOP and CAR-T cell sensitivity. While some archetypes are enriched at diagnosis or relapse, their stability during disease progression remains unclear. We analyzed longitudinal DLBCL cases using LymphoMAP signatures and histologic annotation to assess archetype switching after RCHOP. Methods: We utilized two independent well-annotated DLBCL cohorts with paired diagnosis/relapse biopsies:23 in-house (46 samples) and 44 published cases (88 samples). Gene expression in our cohort was profiled using the NanoString Cancer Immune Panel on fixed (FFPE) specimens. The external dataset comprised whole-transcriptome from FFPE or fresh-frozen samples pre- and post-RCHOP. LymphoMapR predicted the archetypes from normalized counts: enriched in fibroblast and tumor-associated macrophages (FMAC), naïve and memory T cell (LN), activated macrophages and exhausted T cell (TEX). Samples with classification probability <0.7 were excluded. Additionally, we correlated the archetypes with histologic annotation from our cohort. Immunohistochemistry (IHC) supported T cell markers (CD3, CD4, CD8) and PDL1 expression. Multiplex OPAL imaging quantified macrophage markers (CD68, CD163) with immune checkpoint (CD47), and chemokines (CXCL9 and CXCL10) with receptor (CXCR3). Results: In the in-house cohort, 8 patients relapsed following only RCHOP, others received ≥1 relapse regimen. One patient per cohort was excluded for low LymphoMAP confidence. Notably, archetype switching occurred in 13 of 22 patients (59%, 95% CI: 36-79%) in-house and 18 of 43 patients (42%, 95% CI: 28-57%) externally. To gain statistical power, the cohorts were combined, yielding an overall switch rate of 48% (95% CI: 36-60%). Switching was less frequent for patients with LN at diagnosis (38%, 95% CI: 23-57%) than FMAC (59%, 95% CI: 36-78%) or TEX (57%, 95% CI: 33-79%), but no consistent direction of switch or correlation with relapse timing was observed. Germinal center B-cell-like (GCB) DLBCLs were predominantly LN archetype (58%), whereas non-GCB encompassed all LymphoMAP archetypes, suggesting an association with cell-of-origin. Histology was consistent with LymphoMAP prediction: T cell abundance (CD3, CD4, CD8) and CXCR3 expression were highest in TEX, followed by LN and FMAC ( p <0.05). IHC also demonstrated a significant decrease in CD3 and CD8 T cells at relapse compared with diagnosis. Conclusions: Based on our observations, the immune environment of DLBCL is dynamic. Although relapse samples exhibited more T cell-depleted environments, changes in TME archetypes frequently occurred, without a dominant pattern. In the context of patient selection for CAR-T cell therapy, relapsed TME should not be inferred from TME at diagnosis.

利益披露 Disclosure

R. Santiago, None.. R. Aloyz, None.. S. Bianco, None.. S. Dmitrienko, None.. N. Johnson, None.. A. I. Papadakis, None.. N. Benlimame, None.. C. Guilbert, None.. A. Spatz, None.. F. E. Mercier, None.. M. Abraham, None.. L. Hilton, None.. D. W. Scott, None.. K. K. Mann, None.. S. Assouline, None.

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