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

Abstract

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.

PD-L1 and PD-L2 expression in the tumor microenvironment including peritumoral tissue in primary central nervous system lymphoma

“…Our summary of the relevant literature regarding PD-L1 expression in PCNSL is given in Table 4 [3][4][5][6]. The rate of PD-L1 expression varied, ranging from 4.1 to 97%.…”

“…Immune checkpoint inhibitors have thus been expected to provide novel treatment for recurrent/refractory PCNSL. A few studies have already reported the programmed death-ligand 1 (PD-L1) and PD-L2 expression on tumor cells and tumor-infiltrating immune cells in PCNSL [3][4][5][6], but the expression of these two biomarkers in peritumoral tissue remains unclear.…”

PD-L1 and PD-L2 expression in the tumor microenvironment including peritumoral tissue in primary central nervous system lymphoma

“…Our summary of the relevant literature regarding PD-L1 expression in PCNSL is given in Table 4 [3][4][5][6].…”

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) associated with or without lymphoma: Comparison of clinical features and risk factors suggestive of underlying lymphomas

“…Meanwhile, recent clinical trials of the blockade of the programmed death protein 1 (PD-1)/PD-L1 pathway using antibodies demonstrated that this approach had significant efficacy in various malignant tumors, including primary central nervous system lymphomas. Thus, the usage of PD-1/PD-L1 pathway antibodies in CLIPPERS associated lymphoma is worth investigating [63]. Secondly, most CSF proteins originate in the blood serum regardless that a small part of them are synthesized within the CNS or the meninges [64][65][66].…”