Arginase 1 Is a Marker of Myeloid-Mediated Immunosuppression with Prognostic Meaning in Classic Hodgkin Lymphoma

Purpose: Neutrophilia is hallmark of classic Hodgkin Lymphoma (cHL), but its precise characterization remains elusive. We aimed at investigating the immunosuppressive role of high-density neutrophils in HL.

Experimental design: First, N-HL function was evaluated in vitro, showing increased arginase (Arg-1) expression and activity compared to healthy subjects. Second, we measured serum level of Arg-1 (s-Arg-1) by ELISA in two independent, training (N=40) and validation (N=78) sets.

Results: s-Arg-1 was higher in patients with advanced stage (p=0.045), B-symptoms (p=0.0048) and a positive FDG-PET scan after two cycles of chemotherapy (PET-2, p=0.012). Baseline levels of s-Arg-1 >200 ng/mL resulted in 92% sensitivity and 56% specificity to predict a positive PET-2.

Patients showing s-Arg-1 levels > 200 ng/mL had a shorter progression free survival (PFS). In multivariate analysis, PET-2 and s-Arg-1 at diagnosis were the only statistically significant prognostic variables related to PFS (respectively p=0.0004 and p=0.012).

Moving from PET-2 status and s-Arg-1 level we constructed a prognostic score to predict long-term treatment outcome: low s-Arg-1 and negative PET-2 scan (score 0, N=63), with a 3-Y PFS of 89.5%; either positive PET-2 or high s-Arg-1 (score 1, N=46) with 3-Y PFS of 67.6%, and both positive markers (score 2, N=9) with a 3-Y PFS of 37% (p=0.0004).

Conclusions: We conclude that N-HL are immunosuppressive through increased Arg-1 expression, a potential novel potential biomarker for HL prognosis.