Programmed cell death-ligand 1 (PD-L1)(+) tumour cells and low-reacting programmed cell death 1 (PD1)(+) tumour-infiltrating lymphocytes predict poor prognosis in Epstein-Barr virus(+) diffuse large B-cell lymphoma.

Epstein-Barr virus (EBV)+ diffuse large B-cell lymphoma (DLBCL) has specific tumour cell characteristics, and these patients have worse outcomes than EBV-negative DLBCL patients. We compared 38 EBV+ DLBCL patients with 43 methotrexate-associated EBV+ B-cell lymphoproliferative disorders (MTX+/EBV+ BLPDs) and 30 non-germinal centre (GC) subtype DLBCL. Lymphoma cells of the EBV+ DLBCL group were positive for BCL2 in 17 patients (44.7%), CMYC in 23 patients (60.5%), and p53 in 33 patients (86.8%), which was significantly higher than in the MTX+/EBV+ BLPD group (P < 0.05), and were positive for CD30 in 29 patients (76.3%), compared with two in non-GC subtype DLBCL (6.7%) (P < 0.0001). Significantly more EBV+ DLBCL patients (n = 16, 42.1%) had programmed cell death-ligand 1 (PD-L1)+ tumour cells than patients with non-GC subtype DLBCL (n = 5, 16.7%; P = 0.024), and PD-L1+ tumour cells were more common in advanced stages than in early stages (P = 0.048). Twenty-five EBV+ DLBCL patients (69.4%) had few reactive PD1+ tumour-infiltrating lymphocytes (TILs), compared with 12 patients with MTX+/EBV+ BLPDs (37.5%) (P = 0.008). In the EBV+ DLBCL group, CD30, BCL2, CMYC, and p53 expression was not related to patient prognosis. Poor outcomes were associated with PD-L1+ tumour cells (P = 0.001) and low-reacting PD1+ TILs (P = 0.02), while their combination conferred a worse outcome (P < 0.0001). Immune evasion by PD-L1+ tumour cells and exhaustion of PD1+ TILs may occur in EBV+ DLBCL patients, and PD-L1/PD1 interactions may influence tumour progression and poor prognosis.

Kimura S ，Oshiro Y ，Iwasaki H ，Kadowaki M ，Mihashi Y ，Sakata T ，Kawauchi S ，Wang Z ，Takamatsu Y ，Takeshita M ... -  《-》

Clinicopathological evaluation of the programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) axis in post-transplant lymphoproliferative disorders: association with Epstein-Barr virus, PD-L1 copy number alterations, and outcome.

The clinical implications of the programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) axis in patients with post-transplant lymphoproliferative disorders are largely unknown, and its association with Epstein-Barr virus (EBV) status and PD-L1 copy number alterations (CNAs) has not been thoroughly studied. PD1/PD-L1 expression was studied in 50 adult post-transplant lymphoproliferative disorders, and the correlations with PD-L1 CNAs, EBV, clinicopathological features and outcome were evaluated. Thirty-seven (74%) cases were classified as diffuse large B-cell lymphoma (DLBCL), nine (18%) cases were classified as polymorphic, and four (8%) cases were classified as classic Hodgkin lymphoma. Thirty-four cases were EBV-positive, with 29 of 34 (85%) having latency II or III, and 15 of 34 (44%) having viral replication. PD-L1 expression in tumour cells and tumour-associated macrophages was observed in 30 (60%) and 37 (74%) cases, respectively. PD1 positivity was seen in 16 (32%) cases. PD-L1 expression was associated with EBV with latency II or III (P = 0.001) and organ rejection (P = 0.04), and, in DLBCL, with non-germinal centre type DLBCL (P < 0.001). Cases with PD-L1-positive tumour cells showed a higher number of PD-L1 CNAs than PD-L1-negative cases (P = 0.001). Patients with EBV/latency III/replication and simultaneous PD-L1 expression showed the worst overall survival (P < 0.001). The PD1/PD-L1 axis is deregulated in post-transplant lymphoproliferative disorders, with frequent PD-L1 expression and PD1 negativity. PD-L1 expression is associated with EBV latency II or III and PD-L1 CNAs, and probably reflects a proinflammatory tumour microenvironment. The combined analysis of EBV status and PD-L1 expression may help to identify deeply immunosuppressed patients who can benefit from immune reconstitution approaches.

Veloza L ，Teixido C ，Castrejon N ，Climent F ，Carrió A ，Marginet M ，Soldini D ，González-Farré B ，Ribera-Cortada I ，Lopez-Guillermo A ，González-Barca E ，Sierra A ，Herrera M ，Gómez C ，Garcia A ，Balagué O ，Campo E ，Martinez A ... -  《-》

Clinicopathological analysis of programmed cell death 1 and programmed cell death ligand 1 expression in the tumour microenvironments of diffuse large B cell lymphomas.

To investigate the clinicopathological characteristics of programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) expression in the tumour microenvironments of diffuse large B cell lymphoma (DLBCL). Tumour tissues from 126 DLBCL patients were immunostained for PD-L1 and PD-1. The expression of PD-L1 by tumour cells and/or tumour-infiltrating immune cells (mainly macrophages) was evaluated, and the number of tumour-infiltrating PD-1(+) cells was assessed. PD-L1 expression in tumour cells was observed in 61.1% of DLBCLs, with a weak intensity in 29.4%, moderate intensity in 21.4% and strong intensity in 10.3% of cases. Strong PD-L1 expression in tumour cells was associated significantly with the presence of B symptoms (adjusted P = 0.005) and Epstein-Barr virus (EBV) infection (adjusted P = 0.015), and tended to be higher in activated B cell-like immunophenotype (16.7%) than germinal centre B cell-like immunophenotype (2.5%) (adjusted P = 0.271). DLBCLs with PD-L1 expression in tumour cells/macrophages showed similar clinicopathological characteristics. The quantity of PD-1(+) tumour-infiltrating lymphocytes correlated positively with the level of PD-L1 expression in tumour cells (P = 0.042) or in tumour cells/macrophages (P = 0.03). Increased infiltration of PD-1(+) cells was associated with prolonged progression-free survival (P = 0.005) and overall survival (P = 0.026) in DLBCL patients treated with rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), whereas PD-L1 expression had no prognostic significance. PD-L1 and PD-1 were expressed variably in DLBCLs by tumour cells and tumour-infiltrating immune cells and might be potential therapeutic targets using PD-1/PD-L1 blockade.

Kwon D ，Kim S ，Kim PJ ，Go H ，Nam SJ ，Paik JH ，Kim YA ，Kim TM ，Heo DS ，Kim CW ，Jeon YK ... -  《-》

The perivascular microenvironment in Epstein-Barr virus positive primary central nervous system lymphoma: The role of programmed cell death 1 and programmed cell death ligand 1.

It has been shown that high expression of certain immune checkpoint molecules, including those of the programmed death protein 1/programmed death ligand 1 (PD-1/PD-L1) axis, can be utilized to regulate immunosuppression in the microenvironment of malignant neoplasms. For the purpose of clarifying the immune-escape mechanism of primary central nervous system lymphomas (PCNSLs), particularly in Epstein-Barr virus (EBV)-positive cases, markers for PD-1, PD-L1, tumor-associated macrophages (TAMs), and tumor-infiltrating lymphocytes (TILs) in 39 surgical specimens of PCNSLs (17 EBV-positive, 22 EBV-negative) were investigated by immunohistochemistry. Staining for PD-L1 was scored as follows: (-), no staining; (1+), 0-30% positive cells; (2+), 30-60% positive cells; and (3+), >60% positive cells. In EBV-positive cases, PD-L1 was detected in both lymphoma cells and TAMs in 12/17 cases, and in TAMs only in 4/17 cases. The mean number of PD-1, TIA-1 (a marker for cytotoxic T-cells), and FOXP3 (a marker for regulatory T-cells)-positive TILs in EBV-positive cases was 36.4 ± 45.9, 390 ± 603, and 9.88 ± 15.1, respectively. In EBV-negative cases, PD-L1 was detected in both lymphoma cells and TAMs in 11/22 cases, and in TAMs only in 4/22 cases. The mean of PD-1, TIA-1 and FOXP3-positive lymphocytes in EBV-negative cases was 67.3 ± 82.0, 158 ± 206 and 9.32 ± 17.5, respectively. We found no significant difference in the number of FOXP3-positive, lymphocytes between EBV-positive and negative cases. However, there were significantly higher numbers of PD-1-positive lymphocytes in the former, and significantly higher numbers of TIA-1-positive lymphocytes in the latter (P < 0.05). The combined data indicate that expression of PD-L1 by lymphoma cells and TAMs mediate the trafficking of TILs, which may explain the immune-escape process of PCNSLs. In addition, EBV infection appears to affect the trafficking mechanism of TILs, and may thus play an important role in the microenvironment immunity of these tumors.

Sugita Y ，Furuta T ，Ohshima K ，Komaki S ，Miyoshi J ，Morioka M ，Abe H ，Nozawa T ，Fujii Y ，Takahashi H ，Kakita A ... -  《-》

Clinicopathological analysis of primary intestinal diffuse large B-cell lymphoma: Prognostic evaluation of CD5, PD-L1, and Epstein-Barr virus on tumor cells.

Primary intestinal diffuse large B-cell lymphoma (iDLBCL) is rare. In this study, we investigated the clinicopathological features of this disease to further understand the prognostic value of CD5, programmed cell death ligand 1 (PD-L1), and Epstein-Barr virus (EBV) on tumor cells. Tumor specimens from 62 patients consecutively diagnosed with primary iDLBCL at a single institution were analyzed. Our series consisted of EBV-positive (EBV+ ) iDLBCL (n = 10), de novo CD5+ iDLBCL (n = 4), and DLBCL, not otherwise specified (DLBCL-NOS; n = 48). Notably, seven of 10 EBV+ cases had treated lymphoma-associated (n = 4) or iatrogenic immunodeficiency (n = 3). Two of 10 EBV+ cases expressed PD-L1 on tumor cells, whereas the remaining eight were positive for PD-L1 on microenvironment immune cells. Only one DLBCL-NOS case had neoplastic PD-L1 expression with a giant cell-rich appearance. Both EBV-harboring and PD-L1 expression on tumor cells, but not CD5, were associated with worse overall survival (OS) in iDLBCL patients receiving rituximab-containing chemotherapy (P = 0.0354, P = 0.0092, and P = 0.1097, respectively). Multivariate analysis identified PD-L1 positivity on tumor cells (P = 0.0106), PD-L1 negativity on microenvironment immune cells (P = 0.0193), and EBV positivity (P = 0.0324) as poor independent prognostic factors for OS. Among iDLBCL cases without any EBV association, CD5 positivity, or neoplastic PD-L1 expression, high PD-L1 expression (≥40%) on microenvironment immune cells predicted an extremely favorable outcome. EBV+ iDLBCL mainly comprised immunodeficiency-associated patients, which may highlight the specificity of the intestine. PD-L1 expression on tumor cells or microenvironment immune cells was found to have an opposite prognostic impact in iDLBCL.

Ishikawa E ，Kato S ，Shimada K ，Tanaka T ，Suzuki Y ，Satou A ，Kohno K ，Sakakibara A ，Yamamura T ，Nakamura M ，Miyahara R ，Goto H ，Nakamura S ，Hirooka Y ... -  《Cancer Medicine》