The dysregulated lipid metabolism is associated with CD8+ T cell senescence in HIV-associated diffuse large B cell lymphoma

Abstract Backgrounds Our previous study revealed that HIV+ DLBCL patients exhibit senescent-like dysfunction in CD8+ T cells. While it is known that fatty acid metabolism regulates cellular senescence through pathways such as oxidative stress and inflammation, whether fatty acid metabolism is dysregulated in CD8+ T cells of HIV+ DLBCL patients and its potential role in modulating cellular senescence remains unexplored. Methods Gene expression profiling of GSE17372 (13 HIV+ DLBCL tumor) and GSE10846 (414 HIV- DLBCL tumor) from the Gene Expression Omnibus (GEO) database was analyzed to get differentially expressed fatty acid metabolism-related genes (DEFAMRGs). The enrichment analysis and protein-protein interaction (PPI) networks of DEFAMRGs were established. The relative fractions of 22 immune cell types were detected using the “CIBERSORT”. The correlation analysis between DEFAMRGs and immune cells was constructed to discover the potential DEFAMRGs associated with immune cells. Oil red O staining and Nile red staining were used to assess lipid droplets in CD8+ T cells from HIV⁺ DLBCL and HIV⁻ DLBCL patients. Multiplex fluorescence immunohistochemistry (mIHC) and flow cytometry were employed to evaluate CD8⁺ T cell senescence and cytotoxic granule secretion. Cytometric bead array (CBA) was performed to measure senescence-associated secretory phenotype (SASP) in plasma. Correlation analysis was conducted to determine the relationship between lipid droplet accumulation and cellular senescence in CD8⁺ T cells. Results We identified 66 differentially expressed fatty acid metabolism-related genes (DEFAMRGs) between HIV+ DLBCL and HIV- DLBCL tissues, including 27 upregulated and 39 downregulated genes. GO analysis revealed that DEFAMRGs were primarily enriched in pathways related to fatty acid metabolic processes, long-chain fatty acid metabolism and fatty acid biosynthetic processes. KEGG analysis indicated significant enrichment of DEFAMRGs in the PPAR signaling pathway, Rap1 signaling pathway, and fatty acid degradation pathway. Additionally, we identified ten hub FAMRGs in HIV+ DLBCL, including PTGS2, AKT1, APOE, VEGFA, ALOX5, IL-18, PPARa, SPP1, PPIG, and ABCB1. We also observed a decrease in follicular helper T cells, monocytes, naive B cells, resting dendritic cells, eosinophils, and Tregs in the HIV+ DLBCL microenvironment. In contrast, activated memory CD4+ T cells, resting macrophages, plasma cells, and resting NK cells were increased. Correlation analysis demonstrated that the expression of ABCB1 and IL-18 was associated with the proportion of CD8+ T cells, while APOE correlated with CD4+ T cell proportions in HIV+ DLBCL. Meanwhile, lipid accumulation was significantly elevated in CD8+ T cells of HIV+ DLBCL patients. The surface expression of senescence-associated markers CD27 and CD28 decreased, whereas CD57 expression markedly increased. Additionally, the secretion of perforin and granzyme B was significantly reduced. Plasma levels of senescence-associated secretory phenotype (SASP) (IL-8, IL-33) were also notably elevated in HIV+ DLBCL patients. Further correlation analysis revealed that lipid content in CD8+ T cells was positively associated with surface CD27 and CD28 expression but negatively correlated with CD57. Conclusions In this study, we identified ten types of significantly altered immune cells and ten hub DEFAMRGs in HIV+ DLBCL tissues. These DEFAMRGs may contribute to changes in immune cell populations in the tumor microenvironment of HIV+ DLBCL. Additionally, we observed lipid metabolic dysregulation and senescence-associated phenotypes in CD8+ T cells from HIV+ DLBCL patients. The intracellular lipid content was correlated with CD8+ T cell senescence, suggesting that dysregulated lipid metabolism may play a role in promoting CD8+ T cell senescence in HIV+ DLBCL.