Potential Role of Tumor-derived MIF in B-Cell Antigen Presentation in Lung Adenocarcinoma: Single-cell and TCGA Analyses

Background/Aim: Lung adenocarcinoma (LUAD), a predominant subtype of non-small cell lung cancer (NSCLC), is characterized by a complex tumor microenvironment (TME) that drives immune evasion and contributes to variable clinical outcomes. This study investigates the role of tumor-derived macrophage migration inhibitory factor (MIF) on immune modulation and prognosis in LUAD.

Materials and Methods: Single-cell RNA sequencing (scRNA-seq) data from three LUAD tumors (E-MTAB-6149; 29,936 cells) were analyzed with Seurat to identify cell types and marker genes. Cell–cell communication was assessed using CellChat, and prognostic significance was evaluated in the TCGA-LUAD cohort with GEPIA2.

Results: Malignant cells showed the highest expression of MIF, which may interact with CD74⁺CXCR4⁺ and CD74⁺CD44⁺ receptor complexes on B cells, T cells, and myeloid cells, consistent with known MIF-mediated signaling pathways. A predominant B cell subset (59%) expressing CD74 or CXCR4 (termed as MIFR⁺ B cells) showed elevated expression of MHC class II genes (such as HLA-DRA and HLA-DPB1) and co-stimulatory genes (such as CD40 and CD83), indicating antigen-presenting cell (APC)-like functions. High MIF expression was associated with a poor prognosis in TRU-subtype LUAD [hazard ratio (HR)=2.5, p-value=0.029], while MIFR⁺ B cell signatures was correlated with improved survival.

Conclusion: Tumor-derived MIF is associated with poor prognosis, likely by suppressing the immune system, but it also promotes the induction of APC-like B cells, which are associated with improved outcomes, highlighting its dual role in LUAD. These findings position MIF as a potential therapeutic target and suggest that MIFR⁺ B cells could serve as important prognostic markers.