Bone Marrow CD4+ T Cell Depletion Predicts Relapsed Diffuse Large B-Cell Lymphoma

A retrospective investigation published in Cancer Immunology, Immunotherapy indicates that depletion of CD4-positive T cells within the bone marrow immune microenvironment serves as an independent early indicator of treatment failure in patients with diffuse large B-cell lymphoma. Diffuse large B-cell lymphoma, or DLBCL, represents a highly heterogeneous hematologic malignancy in which approximately 30 to 40 percent of individuals progress to relapsed or refractory disease following standard therapeutic intervention. While the bone marrow immune microenvironment has emerged as a promising compartment for identifying early immunological markers of treatment failure, its specific relationship with subsequent disease relapse or refractory progression has historically remained underexplored.

To investigate the immunological alterations linked to treatment outcomes, a research team led by Qiong Zhu, Gang Chen, and colleagues retrospectively analyzed clinical records and bone marrow flow cytometry profiles from a clinical cohort comprising 145 newly diagnosed DLBCL patients. The investigators systematically evaluated bone marrow immune cell distributions at initial diagnosis to identify distinct cellular phenotypes that differentiate patients who eventually experience relapse or refractory progression from those who sustain disease remission. Furthermore, to explore the putative upstream molecular and metabolic mechanisms governing these microenvironmental disruptions, the authors integrated large-scale external public datasets, including transcriptomic profiles from 420 patients in dataset GSE10846 and single-cell RNA sequencing data covering approximately 28,000 cells from dataset GSE182434.

Flow cytometric analysis of the 145 patient bone marrow specimens demonstrated substantial baseline immunological disparities between clinical outcome groups. Patients who subsequently progressed to relapsed or refractory disease exhibited a statistically significant inversion of the bone marrow CD4-to-CD8 T-cell ratio (P = 0.001). This altered ratio occurred alongside a concurrent and marked depletion across several key immune effector populations, including CD4-positive T cells (P < 0.001), natural killer cells (P = 0.005), and natural killer T cells (P = 0.005). These quantitative immunophenotypic observations highlight widespread local immune dysregulation within the bone marrow niche at diagnosis prior to therapy initiation.

Subsequent multivariable statistical modeling confirmed that preserving absolute quantities of bone marrow CD4-positive T cells confers a significant clinical advantage. Specifically, an absolute bone marrow CD4-positive T-cell count of 4,837 cells per microliter or higher emerged as an independent protective factor against the development of relapsed or refractory disease, demonstrating an odds ratio of 0.207 with a 95 percent confidence interval of 0.086 to 0.467 (P < 0.001). In parallel survival evaluations, maintaining a count at or above this threshold proved to be an independent favorable prognostic indicator for progression-free survival, yielding an adjusted hazard ratio of 0.448 with a 95 percent confidence interval of 0.227 to 0.885 (P = 0.021).

To explore the molecular mechanisms potentially orchestrating this systemic lymphoid depletion, the researchers analyzed multi-omics public data resources. The computational evaluation revealed that hypoxia-inducible factor 1-alpha (HIF1A)-driven glycolysis and monocarboxylate transporter 4 (MCT4)-mediated lactate export represented dominant metabolic features associated with systemic immunosuppression. These molecular findings suggest a putative lactate-mediated systemic immunosuppressive axis in DLBCL; however, the authors explicitly noted that these computational hypotheses were not validated in paired clinical tissue samples from their cohort. In addition, baseline serum lactate dehydrogenase (LDH) levels showed no statistically significant correlation with bone marrow CD4-positive T-cell counts among the 145 patients (Spearman rho = -0.098, P = 0.240), underscoring that the hypothesized axis requires direct experimental confirmation.

Translating their immunological observations into an actionable clinical instrument, the research team developed a clinical-immunological nomogram designed for individualized baseline risk estimation. The prognostic nomogram integrates absolute bone marrow CD4-positive T-cell counts alongside standard clinical and pathological risk variables, specifically systemic B symptoms, International Prognostic Index (IPI) scores, and tumor BCL-2 expression status. In performance evaluations, the integrated nomogram achieved an area under the receiver operating characteristic curve (AUC) of 0.797 for predicting subsequent relapsed or refractory progression in newly diagnosed individuals.

In summary, bone marrow CD4-positive T-cell depletion constitutes an independent prognostic indicator of therapeutic resistance and disease relapse in diffuse large B-cell lymphoma. While the proposed lactate-mediated immunosuppressive pathway highlights an important theoretical framework for future experimental and mechanistic studies, the integrated clinical-immunological nomogram provides a practical pre-treatment risk stratification strategy that may assist clinicians in identifying high-risk patients before therapy commences.

Subject of Research: Bone marrow CD4+ T-cell depletion and prognostic modeling in diffuse large B-cell lymphoma

Article Title: Bone marrow CD4 + T cell depletion predicts relapsed/refractory DLBCL and is associated with a putative lactate-mediated systemic immunosuppressive axis

Article References: Zhu, Q., Wang, J.-C., Shi, Y., Lin, W.-Q., Zhao, R.-X., Chen, F.-F., Wang, X.-J., Wang, L., Chen, B.-Z., & Chen, G. (2026). Bone marrow CD4 + T cell depletion predicts relapsed/refractory DLBCL and is associated with a putative lactate-mediated systemic immunosuppressive axis. Cancer Immunology, Immunotherapy. https://doi.org/10.1007/s00262-026-04627-1

Image Credits: AI Generated

DOI: 10.1007/s00262-026-04627-1

Keywords: Diffuse Large B-Cell Lymphoma, DLBCL, Bone Marrow Microenvironment, CD4+ T Cells, Relapsed/Refractory Disease, Flow Cytometry, Progression-Free Survival, Natural Killer Cells, NKT Cells, CD4/CD8 Ratio, Clinical Nomogram, International Prognostic Index, BCL-2 Expression, B Symptoms, HIF1A Glycolysis, MCT4 Lactate Export