Soluble PD-1 but Not PD-L1 Levels Predict Poor Outcome in Patients with High-Risk Diffuse Large B-Cell Lymphoma

SIMPLE SUMMARY: Soluble forms of checkpoint protein PD-1 and its ligand PD-L1 can be measured from circulation, but their source, function, and clinical impact in cancer remain incompletely understood. In this study, we used serum samples collected during a conduction of a prospective immunochemotherapy trial in patients with high-risk diffuse large B-cell lymphoma (DLBCL) and assessed their clinical significance. Our results demonstrate that sPD-1 levels in the peripheral blood at the time of diagnosis correlate with the quantities of tumor infiltrating PD1+ T cells and translate to inferior survival. To our knowledge, this is the first study to identify sPD-1 as a prognostic factor, providing interesting perspectives on future clinical trials in DLBCL, including patients’ stratification associated with checkpoint blockade. ABSTRACT: Interaction of checkpoint receptor programmed death 1 (PD-1) with its ligand 1 (PD-L1) downregulates T cell effector functions and thereby leads to tumor immune escape. Here, we aimed to determine the clinical significance of soluble PD-1 (sPD-1) and soluble PD-L1 (sPD-L1) in patients with diffuse large B-cell lymphoma (DLBCL). We included 121 high-risk DLBCL patients treated in the Nordic NLG-LBC-05 trial with dose-dense immunochemotherapy. sPD-1 and sPD-L1 levels were measured from serum samples collected prior to treatment, after three immunochemotherapy courses, and at the end of therapy. sPD-1 and sPD-L1 levels were the highest in pretreatment samples, declining after three courses, and remaining low post-treatment. Pretreatment sPD-1 levels correlated with the quantities of PD1+ T cells in tumor tissue and translated to inferior survival, while no correlation was observed between sPD-L1 levels and outcome. The relative risk of death was 2.9-fold (95% CI 1.12–7.75, p = 0.028) and the risk of progression was 2.8-fold (95% CI 1.16–6.56, p = 0.021) in patients with high pretreatment sPD-1 levels compared to those with low levels. In conclusion, pretreatment sPD-1 level is a predictor of poor outcome after dose-dense immunochemotherapy and may be helpful in further improving molecular risk profiles in DLBCL.