PO.CL01.16 · 临床研究

血清可溶性 TREM2 预测惰性 B 细胞淋巴瘤不良生存、反映循环 M-MDSC 表面 TREM2 水平并增强 MDSC 介导的 T 细胞增殖抑制

Serum soluble TREM2 predicts poor survival, mirrors surface TREM2 level on circulating M-MDSCs, and enhances MDSC-mediated suppression of T-cell proliferation in indolent B-cell lymphoma

编号 3926 展板 1 时间 4/20 02:00–05:00 区域 Section 48 主讲 Hao-Yuan Wang, MD;PhD

分会场 Prognostic Biomarkers 2

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作者与单位 Authors & Affiliations

Hao-Yuan Wang¹, Po-Chun Liu², Fu-Chen Yang², Ching-Fen Yang³, Chia-Ming Liang⁴, Chia-Ying Wu¹, Chun-Kuang Tsai¹, Po-Shen Ko¹, Yao-Chung Liu¹, Nien-Jung Chen²

¹Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan,²School of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan,³Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan,⁴Department of Surgery, Taoyuan Branch of Taipei Veterans General Hospital, Taoyuan, Taiwan

摘要 Abstract

中文摘要

髓系细胞触发受体 2（TREM2）是一种抗炎性表面受体，具有可溶性异构体（sTREM2）。单核细胞性髓源性抑制细胞（M-MDSC）促进肿瘤生长，我们近期的工作表明，循环 M-MDSC 上高表面 TREM2 可预测弥漫性大 B 细胞淋巴瘤的不良结局。然而，其在惰性 B 细胞淋巴瘤中的作用仍不清楚。本研究调查了初治惰性 B 细胞淋巴瘤中血清 sTREM2 和循环 M-MDSC 表面 TREM2 的临床意义，并在小鼠模型中探讨了其免疫调节作用。这项前瞻性研究纳入了 93 名患者（2019-2025 年）。诊断包括滤泡性淋巴瘤（n=54；33 例低级别，21 例 3A 级）、边缘区淋巴瘤（n=21）、淋巴浆细胞性淋巴瘤（n=6）、小淋巴细胞性淋巴瘤（n=4）和成熟 B 细胞肿瘤（n=8）。中位年龄为 68 岁；46.2% 为男性；58.1% 有骨髓（BM）受累；66.7% 为 Lugano IV 期；21.5% 为高危 IPI。14 名患者接受主动监测，79 名患者接受一线治疗。血清 sTREM2 中位水平为 997 ng/L。循环 M-MDSC 上的标准化表面 TREM2 是相对于配对的健康对照计算的。ROC 分析确定 8.52% 为最佳截断值。高表面 TREM2（>8.52%）与较差的 OS（P=0.031；2 年 OS：84.6% vs 94.5%）和较短的至下次治疗时间（TTNT）（P=0.001；中位：48.69 个月 vs 未达到 [NR]）相关。在主动监测患者（P<0.001；中位：16.87 vs 51.06 个月）和接受一线治疗的患者（P=0.009；中位：48.69 个月 vs NR）中均观察到 TTNT 劣势。血清 sTREM2 水平随标准化表面 TREM2 三分位数升高而增加（中位：694、920 和 2,149 ng/L），较低组与较高组之间（P<0.001）以及中间组与较高组之间（P=0.001）存在显著差异。 ROC 分析确定 1,371 ng/L 为最佳血清 sTREM2 截断值。升高的 sTREM2（>1,371 ng/L）预示较差的 TTNT（P<0.001；中位：48.69 个月 vs NR）和较差的 OS（P=0.002；中位：66.25 个月 vs NR）。为探究 sTREM2 的功能作用，将 CellTrace Violet 标记的小鼠 T 细胞与 WT 或 Trem2 敲除的 BM 来源 MDSC 共培养。在不同的 MDSC:T 细胞比例下，sTREM2 一致地抑制 T 细胞增殖，且在 MDSC 比例较高时抑制作用更强，而 sTREM2 对 Trem2 KO MDSC 的抑制活性比对 WT MDSC 更为显著。总之，升高的血清 sTREM2 与循环 M-MDSC 上较高的表面 TREM2 相关，并预示惰性 B 细胞淋巴瘤的较差生存。初步的小鼠数据表明，sTREM2 增强 MDSC 介导的 T 细胞增殖抑制，支持 sTREM2 在淋巴瘤免疫发病机制中的功能作用。

查看英文原文 English abstract

Triggering receptor expressed on myeloid cells-2 (TREM2) is an anti-inflammatory surface receptor with a soluble isoform (sTREM2). Monocytic myeloid-derived suppressor cells (M-MDSCs) promote tumor growth, and our recent work shows that high surface TREM2 on circulating M-MDSCs predicts poor outcomes in diffuse large B-cell lymphoma. However, its role in indolent B-cell lymphoma remains unclear. This study investigated the clinical significance of serum sTREM2 and surface TREM2 on circulating M-MDSCs in treatment-naïve indolent B-cell lymphoma and explored immunomodulatory effects in murine models. This prospective study enrolled 93 patients (2019-2025). Diagnoses included follicular lymphoma ( n =54; 33 low-grade, 21 grade 3A), marginal zone lymphoma ( n =21), lymphoplasmacytic lymphoma ( n =6), small lymphocytic lymphoma ( n =4), and mature B-cell neoplasms ( n =8). Median age was 68; 46.2% were male; 58.1% had bone marrow (BM) involvement; 66.7% had Lugano stage IV; and 21.5% had high-risk IPI. Fourteen patients received active surveillance, and 79 received first-line therapy. The median serum sTREM2 level was 997 ng/L. Normalized surface TREM2 on circulating M-MDSCs was calculated relative to paired healthy controls. ROC analysis identified 8.52% as the optimal cut-off. High surface TREM2 (>8.52%) was associated with inferior OS ( P =0.031; 2-year OS: 84.6% vs 94.5%) and shorter time to next treatment (TTNT) ( P =0.001; median: 48.69 months vs not reached [NR]). The TTNT disadvantage was observed in both active-surveillance patients ( P <0.001; median: 16.87 vs 51.06 months) and those receiving first-line therapy ( P =0.009; median: 48.69 months vs NR). Serum sTREM2 levels increased across tertiles of normalized surface TREM2 (median: 694, 920, and 2,149 ng/L), with significant differences between lower and higher ( P <0.001) and intermediate and higher groups ( P =0.001). ROC analysis identified 1,371 ng/L as the optimal serum sTREM2 cut-off. Elevated sTREM2 (>1,371 ng/L) predicted inferior TTNT ( P <0.001; median: 48.69 months vs NR) and worse OS ( P =0.002; median: 66.25 months vs NR). To explore the functional roles of sTREM2, CellTrace Violet-labeled murine T cells were cocultured with WT or Trem2 -knockout BM-derived MDSCs. Across varying MDSC:T-cell ratios, sTREM2 consistently suppressed T-cell proliferation, with stronger inhibitory effects at higher proportions of MDSCs, and the suppressive activity of sTREM2 was more pronounced with Trem 2KO MDSCs than WT MDSCs. In conclusion, elevated serum sTREM2 correlates with higher surface TREM2 on circulating M-MDSCs and predicts inferior survival in indolent B-cell lymphoma. Preliminary murine data suggest that sTREM2 augments MDSC-mediated suppression of T-cell proliferation, supporting a functional role for sTREM2 in lymphoma immunopathogenesis.

利益披露 Disclosure

H. Wang, None.. P. Liu, None.. F. Yang, None.. C. Yang, None.. C. Liang, None.. C. Wu, None.. C. Tsai, None.. P. Ko, None.. Y. Liu, None.. N. Chen, None.

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