Integrative multi-omics characterization of KLRB1/CD161 in diffuse large B-cell lymphoma: associations with immune context, subtype biology, and therapeutic response

Background The tumor immune microenvironment (TME) of diffuse large B-cell lymphoma (DLBCL) displays pronounced heterogeneity, and existing immunotherapeutic approaches achieve only suboptimal outcomes for a considerable proportion of affected individuals. CD161—a C-type lectin receptor whose coding gene is KLRB1—has lately emerged as a modulator of T-cell activity in several malignancies; nonetheless, a thorough characterization of its function in DLBCL has not yet been undertaken. Methods Transcriptomic analyses quantified KLRB1 mRNA, whereas flow cytometry and immunoblotting assessed its encoded surface protein, CD161. Transcriptomic, genomic, epigenomic (methylation), and exploratory single-cell RNA-sequencing datasets from DLBCL cohorts were integrated with in vitro functional assays to characterize clinical associations, immune context, and hypothesis-generating therapeutic relationships. Results Pan-cancer analysis revealed predominantly inverse associations between KLRB1 mRNA and immunomodulatory features, whereas DLBCL bulk-tumor analyses showed positive correlations with MHC molecules, immune-cell infiltration estimates, CD8 + T-cell effector programs, and immune-checkpoint transcripts. KLRB1 mRNA was higher in ABC than in GCB DLBCL and was associated with vital status at last follow-up and clinical stage. Lower TIDE scores and pharmacogenomic modeling suggested exploratory, context-dependent relationships with immune-checkpoint blockade and drug response; however, the IMvigor210 urothelial carcinoma cohort showed no significant objective-response difference. Single-cell analyses from two biopsies were exploratory. In OCI-LY3 cells, CD161 manipulation altered MHC-I, phospho-mTOR, cytokine secretion, T-cell activation, and fixed-dose drug-induced apoptosis. These two-biopsy single-cell outputs were not treated as reproducible trajectories or validated intercellular signaling networks, and all functional findings remained specific to the OCI-LY3 model. Conclusion The KLRB1 mRNA/CD161 protein axis is associated with an immune-inflamed DLBCL phenotype and ABC subtype biology. Its prognostic and treatment-predictive value remains hypothesis-generating and requires validation in multivariable survival models, DLBCL-specific immunotherapy cohorts, additional cell lines, and in vivo systems. Confirmation in a GCB cell line and formal dasatinib and doxorubicin dose-response experiments are specifically required.