scholarly journals Histone deacetylase inhibition enhances the therapeutic effects of methotrexate on primary central nervous system lymphoma

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Kenji Fujimoto ◽  
Naoki Shinojima ◽  
Mitsuhiro Hayashi ◽  
Tomoyuki Nakano ◽  
Koichi Ichimura ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cell Viability ◽  
Tumor Cells ◽  
Histone Deacetylase ◽  
Protein Modification ◽  
Histone Deacetylase Inhibitors ◽  
Central Nervous System Lymphoma ◽  
Therapeutic Effects ◽  
Combined Effects

Abstract Background Polyglutamylation is a reversible protein modification that commonly occurs in tumor cells. Methotrexate (MTX) in tumor cells is polyglutamylated and strongly binds to dihydrofolate reductase (DHFR) without competitive inhibition by leucovorin. Therefore, tumor cells with high polyglutamylation levels are supposed to be selectively killed, whereas normal cells with lower polyglutamylation are rescued by leucovorin. This study investigated the combined effects of MTX plus histone deacetylase inhibitors (HDACIs), which upregulate MTX polyglutamylation, in primary central nervous system lymphoma (PCNSL). Methods We evaluated cell viability after MTX treatment and leucovorin rescue and compared the expression of folylpolyglutamate synthetase (FPGS), γ-glutamyl hydrolase (GGH), and DHFR in 2 human PCNSL-derived cell lines (HKBML and TK) and a human Burkitt lymphoma cell line (TL-1). Combination treatments were created using 4 HDACIs: panobinostat, vorinostat, sodium butyrate, and valproic acid. The expression of DHFR was examined as well as ratios of FPGS/GGH expression. The combined effects of MTX plus HDACIs were evaluated using a cell viability assay, mass spectroscopy imaging, and subcutaneous and intracranial xenograft models. Results HDACIs upregulated the ratio of FPGS/GGH expression resulting in increased polyglutamylation of MTX, but also downregulated expression of the target molecule of MTX: DHFR. The combination of MTX and vorinostat decreased cell viability in vitro (P < .05) and tumor volumes in a subcutaneous model (P < .0001), and prolonged survival in an intracranial model (P < .01), relative to controls. Conclusion HDACIs enhanced the therapeutic effect of MTX through increased polyglutamylation of MTX and concomitant downregulation of DHFR expression.

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

2020 ◽  
Author(s):  
Motomasa Furuse ◽  
Hiroko Kuwabara ◽  
Naokado Ikeda ◽  
Yasuhiko Hattori ◽  
Tomotsugu Ichikawa ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Prognostic Significance ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Rank Test ◽  
Biological Factors ◽  
Peritumoral Tissue

Abstract Background: The prevalence of programmed death-ligand 1 (PD-L1) and PD-L2 expression on tumor cells and tumor-infiltrating immune cells in primary central nervous system lymphoma (PCNSL) remains unclear. In the present study, we analyzed needle biopsy and craniotomy specimens of patients with PCNSL to compare the PD-L1 and PD-L2 levels in the tumor and surrounding (peritumoral) tissue. We also assessed the correlation between biological factors and the prognostic significance of PD-L1 and PD-L2 expression. Methods: We retrospectively analyzed the cases of 70 patients histologically diagnosed with PCNSL (diffuse large B-cell lymphoma). Immunohistochemistry for CD20, CD68, PD-L1, and PD-L2 was performed. In cases with specimens taken by craniotomy, the percentages of PD-L1- and PD-L2-positive macrophages were evaluated in both tumor and peritumoral tissue. The Kaplan-Meier method with log-rank test and Cox proportional hazard model were used for survival analysis. Results: The tumor cells expressed little or no PD-L1 and PD-L2, but macrophages expressed PD-L1 and PD-L2 in most of the patients. The median percentage of PD-L2-positive cells was significantly higher among peritumoral macrophages (32.5%; 95%CI: 0–94.6) than intratumoral macrophages (27.5%; 95%CI: 0–81.1, p=0.0014). There was a significant correlation between the percentages of PD-L2-positive intratumoral macrophages and PD-L2-positive peritumoral macrophages (p=0.0429), with very low coefficient correlation (ρ=0.098535). PD-L1 expression on macrophages was significantly associated with biological factors (intratumoral macrophages: better KPS, p=0.0008; better MSKCC score, p=0.0103; peritumoral macrophages: low proportion of LDH elevation, p=0.0064) and longer OS (for intratumoral macrophages: high PD-L1=60 months, 95%CI=30–132.6; low PD-L1=24 months, 95%CI=11–48; p=0.032; for peritumoral macrophages: high PD-L1=60 months, 95%CI=30.7–NR; low PD-L1=14 months, 95%CI=3–26). PD-L1 expression on peritumoral macrophages was strongly predictive of a favorable outcome (HR=0.30, 95%CI=0.12–0.77, p=0.0129). Conclusions: Macrophages in intratumoral and peritumoral tissue expressed PD-L1 and PD-L2 at a higher rate than tumor cells. PD-L1 expression, especially on peritumoral macrophages, seems to be an important prognostic factor in PCNSL. Future comprehensive analysis of checkpoint molecules in the tumor microenvironment, including the peritumoral tissue, is warranted.

scholarly journals Histological verification of the treatment effect of tirabrutinib for relapsed/refractory primary central nervous system lymphoma

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Yoshiko Okita ◽  
Rieko Kano-Fujiwara ◽  
Shin-Ichi Nakatsuka ◽  
Keiichiro Honma ◽  
Manabu Kinoshita
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Tumor Cells ◽  
Central Nervous System Lymphoma ◽  
Pneumocystis Pneumonia ◽  
Resonance Imaging ◽  
Complete Obliteration ◽  
Btk Inhibitor ◽  
First Time ◽  
Histological Verification

AbstractTirabrutinib (ONO/GS-4059; Ono Pharmaceutical) is a newly developed drug that selectively and irreversibly inhibits Bruton’s tyrosine kinase (BTK) and has been approved in Japan for treating relapsed/refractory primary central nervous system lymphoma (PCNSL). However, its therapeutic effect is yet to be verified at the pathological level in human patients. A 64-year-old patient with recurrent PCNSL enrolled in the phase I/II clinical trial of tirabrutinib, a second-generation BTK inhibitor designed for treating relapsed/refractory PCNSL. The left cerebellum lesions on magnetic resonance imaging disappeared one month after tirabrutinib treatment. The patient died because of suspected pneumocystis pneumonia and acute exacerbation of interstitial pneumonia 43 days after starting tirabrutinib. An autopsy confirmed no viable tumor cells in the entire brain, including the left cerebellum lesion, confirming complete obliteration of tumor cells by tirabrutinib. This letter pathologically confirms the effect of tirabrutinib on relapsed/refractory PCNSL for the first time in humans.Trial registration: JapicCTI-173646. Registered 14 July 2017, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-173646.

scholarly journals Stat3-positive tumor cells contribute to vessels neoformation in primary central nervous system lymphoma

Oncotarget ◽  
2017 ◽  
Vol 8 (19) ◽  
pp. 31254-31269 ◽  
Author(s):  
Simona Ruggieri ◽  
Roberto Tamma ◽  
Nicoletta Resta ◽  
Francesco Albano ◽  
Nicoletta Coccaro ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Tumor Cells ◽  
Central Nervous System Lymphoma

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

2019 ◽  
Author(s):  
Motomasa Furuse ◽  
Hiroko Kuwabara ◽  
Naokado Ikeda ◽  
Yasuhiko Hattori ◽  
Tomotsugu Ichikawa ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Tumor Cells ◽  
Immune Escape ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Cancer Center ◽  
Peritumoral Tissue ◽  
The Mean ◽  
Expression Score

Abstract Background: The prevalence of PD-L1 and PD-L2 expression on tumor cells and tumor-infiltrating immune cells in primary central nervous system lymphoma (PCNSL) remains unclear. In the present study, we analyzed needle biopsy and craniotomy specimens of patients with PCNSL to compare the PD-L1 and PD-L2 levels in the tumor and surrounding (peritumoral) tissue. Methods: We retrospectively analyzed the cases of 70 patients histologically diagnosed with PCNSL (diffuse large B-cell lymphoma). Immunohistochemistry for CD20, CD68, PD-L1, and PD-L2 was performed. The PD-L1 and PD-L2 expressions were semi-quantitatively assessed in tumor and peritumoral tissue. Results: The tumor cells expressed little or no PD-L1 and PD-L2, but macrophages expressed PD-L1 and PD-L2 in most of the patients. The PD-L1 expression score was significantly higher in peritumoral macrophages (1.81; 95%CI: 1.52–2.10) than intratumoral macrophages (1.45; 95%CI: 1.26–1.65) (p=0.0456). The mean PD-L2 expression score was significantly higher in peritumoral macrophages (2.07; 95%CI: 1.81–2.33) than intratumoral macrophages (1.52; 95%CI: 1.35–1.70) (p=0.0002). The macrophage expressions of PD-L1 and PD-L2 were significantly correlated in both tumor tissue (p=0.0179) and peritumoral tissue (p=0.020). Neither PD-L1 nor PD-L2 expression was correlated between intratumoral and peritumoral macrophages (PD-L1, p=0.9198; PD-L2, p=0.0659). PD-L1 expression on peritumoral macrophages tended to be associated with a poor Memorial Sloan Kettering Cancer Center score (p=0.0553). Conclusions: Macrophages in intratumoral and especially peritumoral tissue expressed high levels of PD-L1 and PD-L2 and may play an important role in the immune escape mechanism in PCNSL.

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

2019 ◽  
Author(s):  
Motomasa Furuse ◽  
Hiroko Kuwabara ◽  
Naokado Ikeda ◽  
Yasuhiko Hattori ◽  
Tomotsugu Ichikawa ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Prognostic Significance ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Rank Test ◽  
Biological Factors ◽  
Peritumoral Tissue

Abstract Background: The prevalence of programmed death-ligand 1 (PD-L1) and PD-L2 expression on tumor cells and tumor-infiltrating immune cells in primary central nervous system lymphoma (PCNSL) remains unclear. In the present study, we analyzed needle biopsy and craniotomy specimens of patients with PCNSL to compare the PD-L1 and PD-L2 levels in the tumor and surrounding (peritumoral) tissue. We also assessed the correlation between biological factors and the prognostic significance of PD-L1 and PD-L2 expression. Methods: We retrospectively analyzed the cases of 70 patients histologically diagnosed with PCNSL (diffuse large B-cell lymphoma). Immunohistochemistry for CD20, CD68, PD-L1, and PD-L2 was performed. In cases with specimens taken by craniotomy, the percentages of PD-L1- and PD-L2-positive macrophages were evaluated in both tumor and peritumoral tissue. The Kaplan-Meier method with log-rank test and Cox proportional hazard model were used for survival analysis. Results: The tumor cells expressed little or no PD-L1 and PD-L2, but macrophages expressed PD-L1 and PD-L2 in most of the patients. The median percentage of PD-L2-positive cells was significantly higher among peritumoral macrophages (32.5%; 95%CI: 0–94.6) than intratumoral macrophages (27.5%; 95%CI: 0–81.1, p=0.0014). There was a significant correlation between the percentages of PD-L2-positive intratumoral macrophages and PD-L2-positive peritumoral macrophages (p=0.0429), with very low coefficient correlation (ρ=0.098535). PD-L1 expression on macrophages was significantly associated with biological factors (intratumoral macrophages: better KPS, p=0.0008; better MSKCC score, p=0.0103; peritumoral macrophages: low proportion of LDH elevation, p=0.0064) and longer OS (for intratumoral macrophages: high PD-L1=60 months, 95%CI=30–132.6; low PD-L1=24 months, 95%CI=11–48; p=0.032; for peritumoral macrophages: high PD-L1=60 months, 95%CI=30.7–NR; low PD-L1=14 months, 95%CI=3–26). PD-L1 expression on peritumoral macrophages was strongly predictive of a favorable outcome (HR=0.30, 95%CI=0.12–0.77, p=0.0129). Conclusions: Macrophages in intratumoral and peritumoral tissue expressed PD-L1 and PD-L2 at a higher rate than tumor cells. PD-L1 expression, especially on peritumoral macrophages, seems to be an important prognostic factor in PCNSL. Future comprehensive analysis of checkpoint molecules in the tumor microenvironment, including the peritumoral tissue, is warranted.

scholarly journals Sialic acid-binding immunoglobulin-like lectin-15 expression on peritumoral macrophages is a favorable prognostic factor for primary central nervous system lymphoma patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hirotaka Fudaba ◽  
Yasutomo Momii ◽  
Taisei Hirakawa ◽  
Kouhei Onishi ◽  
Daigo Asou ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Overall Survival ◽  
Nervous System ◽  
Sialic Acid ◽  
Tumor Cells ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Sialic Acid Binding ◽  
Cox Analysis

AbstractSialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) is a new immune checkpoint molecule and its role of primary central nervous system lymphoma (PCNSL) tumor microenvironment has been unclear. We explored the Siglec-15 and programed death-ligand 1 (PD-L1) expression in tumor tissues and analyzed the association between the expression of these molecules and overall survival in newly diagnosed PCNSL. A total of 60 patients diagnosed with diffuse large B-cell lymphoma in PCNSL were included in this study. The Siglec-15 and PD-L1 expression on tumor cells, intratumoral macrophages and peritumoral macrophages were immunohistochemically evaluated. The expression of Siglec-15 and PD-L1 was greater in macrophages than in tumor cells. Regarding peritumoral macrophages, the number of Siglec-15-positive samples (n = 24) was greater than the number of PD-L1-positive samples (n = 16). A multivariate Cox analysis showed that the Siglec-15 positivity of peritumoral macrophages and performance of high-dose methotrexate-based chemotherapy were independent predictors of overall survival (hazard ratio: 0.295 and 0.322, respectively). The Kaplan–Meier survival curves showed that patients with Siglec-15-positive peritumoral macrophages had longer overall survival than those with Siglec-15-negative peritumoral macrophages (median overall survival: 3018 days and 746 days, respectively; p = 0.0290). Our findings indicate that the expression of Siglec-15 on peritumoral macrophages induces a favorable outcome in PCNSL patients.

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