https://orcid.org/0000-0003-0681-0998
Key Points
CD8MMR integrates pre-treatment tumor immunity into risk stratification for DLBCL patients.
Low CD8MMR is linked to poor survival and adds prognostic value beyond IPI and cell-of-origin in DLBCL.
Abstract
CD8 and CD4 T lymphocytes play critical roles in antitumor immunity and are central to immune-based therapies for diffuse large B-cell lymphoma (DLBCL). Conversely, monocytic myeloid-derived suppressor cells (M-MDSCs) promote immunosuppression and tumor progression. This study investigates the prognostic value of the ratios of CD8 and CD4 T lymphocytes to M-MDSCs—referred to as CD8MMR and CD4MMR—in untreated DLBCL patients. In a prospective observational study, 160 newly diagnosed DLBCL patients were enrolled and randomized into training (n=120) and validation (n=40) cohorts. Circulating immune cells were assessed from fresh peripheral blood using flow cytometry, and cutoff values for CD8MMR and CD4MMR were determined by ROC curve and AUC analysis. Patients with high-risk International Prognostic Index (IPI), double-expressor lymphoma, or EBV-positive DLBCL had significantly lower CD8MMR and CD4MMR. Low CD8MMR (<3.56) or CD4MMR (<3.79) was significantly associated with inferior progression-free survival (PFS) and overall survival (OS). When combining both ratios, patients with high levels of CD8MMR and CD4MMR had the most favorable survival, while those with low levels of both had the poorest outcomes; discordant levels corresponded to intermediate survival. Multivariate analysis revealed CD8MMR as an independent predictor of PFS and OS, with greater predictive strength than CD4MMR. Furthermore, CD8MMR stratified survival outcomes across different IPI risk categories and cell-of-origin subtypes, consistently identifying patients with poor prognosis. These findings suggest that CD8MMR is a novel and independent prognostic biomarker in DLBCL, offering additional value for risk stratification in clinical practice.
Author notes
Availability of data and materials
The datasets analyzed during this study are available upon reasonable request in accordance with our hospital's IRB regulations.
Translational Relevance
The lymphocyte-to-monocyte ratio (LMR) has been recognized as a prognostic marker for DLBCL for about a decade, with a low LMR associated with poor outcomes. CD8 T lymphocytes serve as crucial effector cells in modern cell-and-immune therapies targeting DLBCL, whereas M-MDSCs are well-known for their immunosuppressive properties that promote tumor development. Our study refines the concept of LMR by identifying CD8MMR as a more specific and biologically grounded biomarker, where CD8 T lymphocytes represent anti-lymphoma activity, and M-MDSCs represent pro-lymphoma activity. Analogous to a seesaw, CD8MMR reflects the balance between these opposing forces. We demonstrate that low CD8MMR is strongly associated with worse PFS and OS and provides additional prognostic value within IPI risk groups and cell-of-origin subtypes. Integrating CD8MMR into clinical practice could enhance risk stratification and guide personalized treatment strategies, identifying high-risk patients who may potentially benefit from intensified therapies or novel immunotherapies.
