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. 2025 May 28;25(1):959.
doi: 10.1186/s12885-025-14359-7.

Toll-like receptor 9 (TLR9) expression correlates with cell of origin and predicts clinical outcome in diffuse large B-cell lymphoma

Sulaf Abd Own  1   2 , Ioanna Xagoraris  3   4 , Konstantina Stathopoulou  4 , Björn E Wahlin  5   6 , Weicheng Ren  7 , Mehran Ghaderi  8 , Qiang Pan-Hammarström  7 , Birgitta Sander #  3   8 , Karin E Smedby #  9   5 , Georgios Rassidakis #  3   4
Affiliations

Toll-like receptor 9 (TLR9) expression correlates with cell of origin and predicts clinical outcome in diffuse large B-cell lymphoma

Sulaf Abd Own et al. BMC Cancer. .

Abstract

Background: Biological insights beyond the cell-of-origin (COO) classification can support clinical management in diffuse large B-cell lymphoma (DLBCL). We investigated if Toll-like receptor 9 (TLR9) expression could serve as a prognostic marker in DLBCL.

Method: TLR9 gene expression was analysed in four publicly available cohorts (n = 2474), and protein expression was investigated in germinal centre B-cell (GCB) and activated B-cell (ABC) DLBCL cell lines. Next, TLR9 protein expression was analysed in 120 diagnostic samples from R-CHOP-treated patients with relapsed/refractory disease (poor outcome, n = 50) or in complete remission (good outcome, n = 70). Associations were evaluated using logistic regression, estimating odds ratios (OR) and 95% confidence intervals (CI).

Results: TLR9 gene expression was higher in ABC DLBCL compared to GCB DLBCL in external cohorts, and similar results were obtained for protein expression in cell lines. In patient samples, high TLR9 protein expression correlated with non-GCB type (p = 0.003) and poor outcome (p = 0.0016). High TLR9 expression remained associated with poor outcome in multivariable analysis after adjusting for COO and other clinical features (OR = 3.36, 95% CI 1.41-8.04). In exploratory analyses, a decrease of cell growth in ABC cell lines following inhibition of TLR9 activity with ODN4084-F was suggested.

Conclusion: We conclude that TLR9 correlates with ABC/non-GCB phenotype and is a potential predictor of poor prognosis in DLBCL.

Keywords: Biomarker; DLBCL; Prognosis; TLR9.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The regional ethics committee in Stockholm approved the study (Dnr 2015/2028–31/2). The authors confirmed that all experiments using human tissue samples were performed in accordance with relevant guidelines and regulations. Written informed consent was obtained from living participants. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
A TLR mRNA expression levels were assessed in GSE10846, phs001444, GSE117556, and GSE181063 cohorts by cell of origin. TLR9 genes are highly expressed in ABC (p < 0.001) compared to GCB. B TLR9 mRNA expression levels were assessed in the four cohorts by genetic subtypes according to the Wright et al. classifier [3]. There was a higher TLR9 expression in MCD, N1 and A53 subtypes compared to EZB subtype. C Kaplan–Meier survival analysis revealed that higher TLR9 expression was associated with poorer overall survival (OS) and progression-free survival (PFS) across different cohorts. Patients were stratified as follows: within each cohort, the high-expression group comprised the top 25% of patients with the highest TLR9 expression
Fig. 2
Fig. 2
TLR9 protein expression on cell lines assessed by western blot (upper left panel) and measured by band density in (lower left panel). TLR9 immunohistochemical stains (right panel). Cell lines include Diffuse large B-cell lymphoma (DLBCL) activated B-cell (ABC) type (OCI-LY3 and U2932), germinal-centre B-cell (GCB) type (MS and RCK8), Mantle cell lymphoma (MCL) and (Granta519 and Z138). Higher expression of TLR9 in ABC compared to GCB
Fig. 3
Fig. 3
Immunohistochemical stain of TLR9 expression in DLBCL using monoclonal anti-TLR9 antibody distinguishing low (left) and high expression (right)
See this image and copyright information in PMC

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