Programmed Death-1 and Programmed Death-Ligand 1 Expression Patterns in Pediatric Lymphoma

Introduction The programmed death-1 (PD-1)-programmed death-ligand 1 (PD-L1) pathway is an inhibitory immune checkpoint that can suppress T-cell-mediated tumor cytotoxicity. Anti-PD-1 monoclonal antibodies have recently been recognized as promising therapy for adult patients with lymphoma, particularly in classical Hodgkin's lymphoma. However, little information is available regarding the expression patterns of PD-1 and PD-L1 in pediatric lymphoma. Therefore, this study aimed to investigate the expression patterns of PD-1 and PD-L1 in pediatric lymphoma. Methods Immunohistochemical analysis was performed on paraffin-embedded pretherapeutic tumor biopsies from 36 newly diagnosed pediatric patients (aged 0-15 years) with lymphoma or lymphoproliferative disorders treated at Kobe Children's Hospital (Kobe, Japan) from 2003 to 2018. Results Thirty-six samples comprising 11 of Burkitt lymphoma (BL), 7 of anaplastic large-cell lymphoma (ALCL), 6 of T-lymphoblastic lymphoma (T-LBL), 5 of diffuse large B-cell lymphoma (DLBCL), 3 of Hodgkin's lymphoma (HL), 2 of chronic active EBV-associated lymphoproliferative disorders (CAEBV-LPD), 1 of T cell/histiocyte rich B-cell lymphoma (T/HRBCL), and 1 of subcutaneous panniculitis-like T-cell lymphoma (SPTCL) were evaluated. PD-L1 and PD-1 staining results in each lymphoma type are explained below and in Table. Burkitt lymphoma None of the 11 samples stained for PD-L1 or PD-1 in BL cells. PD-1 was expressed in a small proportion of tumor-infiltrating lymphocytes (TIL) in 3 of the 11 samples. Anaplastic large-cell lymphoma PD-L1 was robustly expressed in ALCL cells in 5 of the 7 samples. However, PD-1 was not expressed in any ALCL cell samples but expressed in a small proportion of TIL in only 1 sample. T-lymphoblastic lymphoma None of the 6 samples stained for PD-L1 in T-LBL cells. PD-1 was stained in T-LBL cells in only 1 sample. Moreover, PD-1 was not stained in TIL in any samples. Diffuse large B-cell lymphoma None of the 3 samples with DLBCL-not otherwise specified (DLBCL-NOS) or 1 sample with DLBCL with IRF4 rearrangement expressed PD-L1 on tumor cells. Conversely, PD-L1 was overexpressed in tumor cells in 1 sample with DLBCL with an interfollicular pattern of proliferation (DLBCL-IF). However, PD-1 was not expressed in any DLBCL cell samples. PD-1 was expressed in a small proportion of TIL in 1 sample with DLBCL with IRF4 rearrangement. Hodgkin's lymphoma PD-L1 was overexpressed in HL cells in both nodular sclerosis classic HL (NScHL), whereas PD-L1 was not expressed in nodular lymphocyte predominant HL (NLPHL) cells. PD-1 was not expressed in HScHL or NLPHL cells but was expressed in a small proportion of TIL in 1 sample with NLPHL. Chronic active EBV-associated lymphoproliferative disorders PD-L1 was overexpressed in tumor cells in both samples with CAEBV-LPD. PD-1 was not expressed in tumor cells but was expressed in a small proportion of TIL in 1 sample. T cell/histiocyte-rich B-cell lymphoma PD-L1 was overexpressed on tumor cells in T/HRBCL. PD-1 was weakly expressed in a part of T/HRBCL cells but strongly expressed in TIL. Subcutaneous panniculitis-like T cell lymphoma PD-L1 was overexpressed in tumor cells in SPTCL. However, PD-1 was not expressed in SPTCL cells or TIL. Discussion In this pediatric cohort, PD-L1 was overexpressed in tumor cells in ALCL (5/7), DLBCL-IF (1/1), NScHL (2/2), CAEBV-LPD (2/2), T/HRBCL (1/1), and SPTCL (1/1), but not in BL, T-LBL, DLBCL-NOS, or NLPHL. While the PD-L1 expression in EBV-positive lymphoma cells has been reported before, this study demonstrated the PD-L1 overexpression in CAEBV-LPD. In addition, we demonstrated the PD-L1 overexpression on SPTCL and DLBCL-IF cells, whereas the PD-L1 overexpression in T/HRBCL cells was consistent with previous reports. This study demonstrated that the PD-1 expression in tumor cells was rare in pediatric lymphoma. In addition, PD-1 expressions in TIL tended to be low in pediatric lymphoma, except for NLPHL and T/HRBCL. Besides classic HL, PD-1 blockade might be a promising treatment strategy for ALCL, DLBCL-IF, CAEBV-LPD, T/HRBCL, and SPTCL in children. Indeed, anectodal reports showed promising efficacy in ALCL. Therefore, further investigations are required to assess the role of the PD-1-PD-L1 pathway in pediatric lymphoma. No relevant conflicts of interest to declare.