Abstract
Simple SummarySoluble 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.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.
Highlights
Two-thirds of patients with diffuse large B-cell lymphoma (DLBCL) are cured in response to standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-based immunochemotherapy [1]
Our study demonstrates that high soluble PD-1 (sPD-1) levels in peripheral blood at the time of diagnosis are associated with poor survival in patients diagnosed with clinically high-risk DLBCL treated uniformly in a multicenter clinical trial
Earlier studies showed that pretreatment soluble programmed death ligand 1 (PD-L1) (sPD-L1) levels correlate with poor outcome in DLBCL patients treated with R-CHOP immunochemotherapy
Summary
Two-thirds of patients with diffuse large B-cell lymphoma (DLBCL) are cured in response to standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-based immunochemotherapy [1]. Treatment options for primary refractory and relapsed patients are few, and the disease is often fatal. If molecular factors determining the poor prognosis were understood better, targeted therapies could be applied to improve outcomes in these patients and to avoid overtreatment. Recent comprehensive genome and transcriptome studies elucidated the heterogeneity of DLBCL and revealed multiple DLBCL subtypes with different outcomes [2,3,4]. In addition to tumor-cell-derived factors, an association between tumor microenvironment (TME) and survival was identified. Among the most essential prognostic microenvironmental factors are tumor-infiltrating T cells (TILs) [5,6,7]
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