Tumor-associated macrophages (CD68+) as a potential prognostic biomarker for PD-1 inhibitor response in relapsed/refractory classical Hodgkin lymphoma

Abstract Objective: Despite the significant clinical efficacy of PD-1 blockade in relapsed or refractory classical Hodgkin lymphoma (R/R cHL), its underlying mechanisms remain incompletely understood, largely due to the complex tumor microenvironment (TME). Reliable predictive biomarkers are currently lacking. This study investigated potential TME-based prognostic indicators for response to PD-1 antibody therapy in cHL to advance personalized treatment strategies. Methods: We conducted a retrospective analysis of 40 R/R cHL patients treated with PD-1 antibodies at the First Affiliated Hospital of Zhengzhou University. Clinical data and follow-up information were collected. The expression of key immune markers (CD8+ cytotoxic T cells, CD68+ macrophages, FOXP3+ Tregs, PD-1, PD-L1, PD-L2) in pretreatment tumor tissues was quantified using immunohistochemistry and average optical density (AOD) measurements. Results: AOD values for all six markers (CD8, CD68, FOXP3, PD-1, PD-L1, PD-L2) showed no significant association with baseline clinical characteristics (age, gender, histology, stage, B symptoms, IPS score, LDH level, bulky disease, number of involved nodal areas, EBER status). However, higher CD68 AOD was significantly associated with improved objective response rate (ORR) (P=0.013). AOD values for CD8, FOXP3, PD-1, PD-L1, and PD-L2 showed no association with ORR. Using median AOD values to distinguish patients into high expression and low expression groups, univariate survival analysis revealed that high CD68 expression was significantly associated with prolonged progression-free survival (PFS) following PD-1 inhibitor therapy (P=0.046). Conclusion: Quantitative assessment of CD68+ tumor-associated macrophage density via AOD measurement is associated with improved treatment response and PFS in R/R cHL patients receiving PD-1 inhibitors. Pretreatment evaluation of CD68 expression in pathological tissues may serve as a valuable prognostic biomarker to guide PD-1 inhibitor therapy selection in cHL.