High levels of soluble TREM2 predict poor survival outcomes and facilitate the expansion of immunosuppressive monocytic-lineage cells in patients with DLBCL. Free

: Triggering receptor expressed on myeloid cells-2 (TREM2) is a surface receptor with anti-inflammatory properties, known to promote M2-type macrophage polarization. We recently identified that surface TREM2 is expressed on monocytic myeloid-derived suppressor cells (M-MDSCs) in DLBCL patients, and that elevated surface-TREM2 levels are associated with inferior survival outcomes.

Beyond its membrane-bound form, a soluble isoform of TREM2 (sTREM2) has been shown to support microglial survival in murine models of neurodegenerative diseases. However, the role of sTREM2 in the lymphoma microenvironment remains unclear. Therefore, this study investigates the clinical significance of serum sTREM2 levels in treatment-naïve DLBCL patients and explores its potential immunomodulatory effects through preliminary murine models.

Methods: This prospective observational study enrolled 160 treatment-naïve DLBCL patients at Taipei Veterans General Hospital between May 15, 2019, and November 30, 2023. Patients with primary CNS or mediastinal B-cell lymphoma were excluded. The final follow-up was completed on October 1, 2024.

Serum sTREM2 levels were quantified by ELISA. Flow cytometry was used to characterize peripheral blood monocytic-lineage populations: M-MDSCs (CD45⁺ CD15⁻ CD14⁺ CD11b⁺ CD33⁺ HLA-DR^low/⁻) and HLA-DR⁺ monocytes (same markers but HLA-DR⁺). CD14 IHC staining was performed on formalin-fixed paraffin-embedded tissues using an AP/Red detection system.

To assess sTREM2's effect on cell survival, murine BM cells were differentiated into BM-derived MDSCs and M-CSF-induced monocytes (M0 MBMMs), followed by growth factor withdrawal and treatment with murine recombinant sTREM2 (0, 600, 6000 ng/mL). Apoptosis was measured by BrdU and 7AAD staining via flow cytometry, with BrdU^–7AAD^low cells considered apoptotic (Sub-G1 phase).

Results: Among 160 enrolled DLBCL patients (median age: 69), 40.6% had stage IV disease, 33.8% were high-risk IPI, 26.3% had BM involvement, 72.5% were non-GCB subtype, and 41.9% had double-expressor lymphoma (DEL). The median serum sTREM2 level was 1,393 ng/L.

Older patients (≥70 years) had significantly higher sTREM2 levels than younger patients (1,642 vs. 1,259 ng/L, P = 0.010). Patients with high-risk IPI also had elevated sTREM2 levels compared to low/intermediate-risk groups (2,265 vs. 1,259 ng/L, P < 0.001).

Based on ROC-AUC analysis, a cutoff of 2,000 ng/L stratified patients into high and low sTREM2 groups. High sTREM2 levels predicted significantly worse survival (2-year PFS: 48.2% vs. 77.3%, P < 0.001; 2-year OS: 56.3% vs. 84.5%, P < 0.001).

Multivariate Cox regression identified high sTREM2 as an independent predictor of poor PFS (HR = 2.382; 95% CI: 1.359–4.173) and OS (HR = 2.645; 95% CI: 1.412–4.953) after adjusting for age, sex, IPI risk, BM involvement, non-GCB subtype, DEL subtype, and EBV-positive DLBCL.

High sTREM2 levels (>2,000 ng/L) were significantly associated with increased circulating M-MDSCs (2.14% vs. 0.97%, P < 0.001) and HLA-DR⁺ monocytes (4.72% vs. 2.94%, P < 0.001). Among the 86 DLBCL patients with analyzable lymph-node tumor tissues, elevated sTREM2 levels also correlated with greater infiltration of CD14⁺ monocytic-lineage cells within the lymphoma microenvironment.

In vitro murine studies showed that sTREM2 significantly reduced apoptosis (BrdU^– 7AAD^low) in both BM-MDSCs and M0 MBMMs after growth factor withdrawal. The anti-apoptotic effect was more pronounced in Trem2-KO cells than in WT counterparts, suggesting that exogenous sTREM2 compensates for the absence of endogenous sTREM2 release.

Conclusion: Elevated serum sTREM2 levels in treatment-naïve DLBCL patients independently predict inferior PFS and OS. High sTREM2 correlates with increased circulating M-MDSCs, HLA-DR⁺ monocytes, and CD14⁺ cell infiltration in lymphoma tissues. Preliminary murine data suggest that sTREM2 enhances the survival of monocytic-lineage cells by attenuating apoptosis, potentially contributing to the expansion of immunosuppressive subsets. These findings support a functional role for sTREM2 in lymphoma immunopathogenesis and warrant further mechanistic investigation.