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

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.