LYMPHOCYTE EXHAUSTION IN RELAPSED HODGKIN LYMPHOMA: AN INVESTIGATIVE STUDY

Abstract

Relapsed or refractory classical Hodgkin lymphoma (R/R cHL) remains a formidable clinical challenge, with many patients exhibiting poor responses to second-line therapies despite recent advances in immunotherapy. This study investigates the immunological landscape of T cell exhaustion as a mechanism underpinning therapeutic resistance in relapsed Hodgkin lymphoma. Peripheral blood and tumour biopsy samples were analysed from patients with relapsed cHL using multiparametric flow cytometry, cytokine profiling, and transcriptomic data mining. T cell exhaustion was evaluated based on phenotypic expression of inhibitory receptors (PD-1, CTLA-4, TIM-3, LAG-3), functional cytokine output (IFN-γ, TNF-α, IL-2), and gene expression analyses (TOX, NR4A1, BATF) from publicly available datasets. Flow cytometry revealed significantly increased expression of exhaustion markers on both CD8+ and CD4+ T cells in relapsed patients, with PD-1 showing the highest expression levels. The ability of T cells to produce effector cytokines was substantially lower in the relapsed group than in healthy donor samples. Analysis of mRNA expression showed significant overexpression of genes known to regulate T cell exhaustion, with p-values < 0.005. Immune analysis showed greater numbers of regulatory T cells and lower levels of activated CD8+ T cells in the tumour microenvironments of relapsed samples. The findings demonstrate that relapsed Hodgkin lymphoma is characterized by a profoundly exhausted T cell phenotype driven by changes at both the phenotype, functional and transcriptomic levels. These results demonstrate the multi-faceted nature of immune escape in cHL and call for innovative combination immune therapies that directly counter exhaustion mechanisms to enhance outcomes for patients.