Immunosenescence phenotypes and prognostic significance of CD8 + CD28− T cells in AIDS-related non-Hodgkin lymphoma

AIDS-related non-Hodgkin lymphoma (AR-NHL), a leading malignancy among people living with HIV (PLWH), may not receive standard intensive curative therapies as the general population due to immune deficiency concerns, even in the combined antiretroviral therapy (cART) and immunochemotherapy era. Thus, a comprehensive understanding of T-cell subsets landscapes is urgently needed to grasp the complex and dynamic role of the immune system in AR-NHL patients' survival. This longitudinal cohort study enrolled 31 de novo adult AR-NHL patients and 52 HIV-negative NHL controls. Multi-color flow cytometry profiled peripheral blood immunophenotypes at baseline and during immunochemotherapy. Univariate and multivariate Cox regression analyses evaluated associations between baseline risk factors and clinical outcomes. AR-NHL patients exhibited comparable 1-year overall survival (71.0% vs. 74.8%) and progression-free survival (60.4% vs. 64.6%) to HIV-negative NHL individuals. Baseline β2-microglobulin (β2-MG), erythrocyte sedimentation rate, and EBER positivity were higher in AR-NHL. AR-NHL revealed persistent immune senescence during immunochemotherapy, including reduced CD4+ T cells, lower CD4/CD8 ratio, decreased Tregs, naïve CD45RA+, and memory CD45RO + CD4+ T cells, alongside elevated Tregs/CD4, CD8+, CD8 + CD28+, and CD8 + CD28- T cells, highlighting the complex HIV-driven immune compromise. Multivariate analysis identified baseline circulating CD8 + CD28- T cells as an independent predictor of inferior prognosis in AR-NHL, correlated with aggressive disease markers such as elevated β2-MG, hypoproteinemia, decreased CD4/CD8 ratio, high International Prognostic Index score, and EBER positivity. AR-NHL patients warrant standard full-dose cancer therapy to improve prognosis despite immunocompromised and immunosenescence phenotypes. CD8 + CD28- T cells serve as an independent prognostic biomarker for AR-NHL, potentially associated with chronic immune activation and viral exposure. Our data suggest that characterizing T-cell subsets may enhance understanding of immune dynamics in AR-NHL, providing a foundation for exploring personalized approaches to infection prophylaxis.