The Significance of Pd‐l1 and Pd1 Receptors Expression in Patients With Diffuse B‐cell Large‐cell Lymphoma

Abstract

Introduction: diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphomas (NHLs).Standard chemoimmunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) is able to cure a significant proportion of patients; however, 30% of total cases experience relapse or have refractory disease. The international prognostic index (IPI) represents the most useful prognostic score, but it is exclusively based on clinical parameters. Previous studies showed the microenvironment has a prognostic influence in DLBCL cases; among its cellular components, tumor-associated macrophages (TAM) surely play a leading role. TAM can be classified into 2 distinct types, M1 (anti-tumor activity) and M2 (protumor activity). Another prognostic factor could be represented by lymphopenia, measured as lymphocyte-to-monocyte and neutrophil-to-lymphocyte ratio (LMR and NLR), that reflects a reduced host systemic immunity.Methods: in this study we would like to evaluate the prognostic impact of total TAM, M1 and M2 subtypes, LMR and NLR in newly diagnosed DLBCL patients. The primary objective is represented by progression-free survival (PFS). Secondary objectives are complete remission (CR) rate and overall survival (OS). We have retrospectively analyzed a cohort of 37 consecutive newly diagnosed DLBCL patients, treated between 2009 and 2013. Out of 37 patients, 28/37 (75.6%) received R-CHOP or CHOP-like regimens, 9/37 (24.4%) were treated with less intensive therapies.Treatment response was assessed according to 2007 revised criteria. Immunohistochemistry stainings were performed on paraffin-embedded sections with antibodies against CD68 (PG-M1 clone, 1:50, Dako) and CD163 (1:200, Novocastra-Leica). We have evaluated total TAM (CD68+ and CD163+) and different subtypes (CD68+, CD163+, CD68+/CD163+). We have divided our cohort in 2 categories as previously published by Steidl and colleagues; score 1-2 represented the group with low expression, while score 3 represented the group with high expression. TAM with the expression of both CD68 and CD 163 were considered as M2. For LMR and NLR we used previouly published cut-off of 2.71 and 2.81, respectively.Results: CR rate was 70.3% (26/37 cases), 11 cases did not achieve an adequate response (5 PR, 4 SD, 2 PD). We did not report a significant correlation between total TAM, CD68+ TAM, CD163+ TAM, CD68+/CD163+ TAM, LMR, NLR and CR. We observed an association between lower expression of M2 TAM, higher expression of CD68+ TAM and improved PFS and OS, even if it did not reach a statistical significance. Conclusion: our study suggests TAM CD68+ and especially M2 TAM could have a prognostic role for DLBCL cases receiving R-CHOP; the lack of statistical significance could be due to the small sample size. Multicenter prospective studies are needed to compare and standardize all the different available scoring methods, with the aim to perform in the future TAM evaluation at diagnosis in daily clinical practice. Keywords: diffuse large B-cell lym...