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PD-L1 Monoclonal Antibody Treats Ischemic Stroke by Controlling Central Nervous System Inflammation.

ABSTRACT: BACKGROUND AND PURPOSE:Both pathogenic and regulatory immune processes are involved in the middle cerebral artery occlusion (MCAO) model of experimental stroke, including interactions involving the programmed death 1 (PD-1) receptor and its 2 ligands, PD-L1 and PD-L2. Although PD-1 reduced stroke severity, PD-L1 and PD-L2 appeared to play pathogenic roles, suggesting the use of anti-PD-L monoclonal antibody therapy for MCAO. METHODS:Male C57BL/6 mice were treated with a single dose of anti-PD-L1 monoclonal antibody 4 hours after MCAO and evaluated for clinical, histological and immunologic changes after 96 hours of reperfusion. RESULTS:Blockade of the PD-L1 checkpoint using a single injection of 200 ?g anti-PD-L1 monoclonal antibody given intravenously 4 hours after occlusion significantly reduced MCAO infarct volumes and improved neurological outcomes after 96 hours of reperfusion. Treatment partially reversed splenic atrophy and decreased central nervous system infiltrating immune cells concomitant with enhanced appearance of CD8(+) regulatory T cells in the lesioned central nervous system hemisphere. CONCLUSIONS:This study demonstrates for the first time the beneficial therapeutic effects of PD-L1 checkpoint blockade on MCAO, thus validating proposed mechanisms obtained in our previous studies using PD-1- and PD-L-deficient mice. These results provide strong support for the use of available humanized anti-PD-L1 antibodies for treatment of human stroke subjects.

SUBMITTER: Bodhankar S

PROVIDER: S-EPMC4589506 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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PD-L1 Monoclonal Antibody Treats Ischemic Stroke by Controlling Central Nervous System Inflammation.

Bodhankar Sheetal S Chen Yingxin Y Lapato Andrew A Dotson Abby L AL Wang Jianming J Vandenbark Arthur A AA Saugstad Julie A JA Offner Halina H

Stroke 20150825 10

<h4>Background and purpose</h4>Both pathogenic and regulatory immune processes are involved in the middle cerebral artery occlusion (MCAO) model of experimental stroke, including interactions involving the programmed death 1 (PD-1) receptor and its 2 ligands, PD-L1 and PD-L2. Although PD-1 reduced stroke severity, PD-L1 and PD-L2 appeared to play pathogenic roles, suggesting the use of anti-PD-L monoclonal antibody therapy for MCAO.<h4>Methods</h4>Male C57BL/6 mice were treated with a single dos ...[more]

PMID: 26306753

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Project description:CD20-negative diffuse large B-cell lymphoma (DLBCL) is a rare type of lymphoproliferative disorder characterized by a high degree of aggressiveness, a tendency for extranodal invasion and chemotherapeutic resistance. CD20-negative DLBCL originating from the nervous system is rarer. In primary central nervous system lymphoma (PCNSL), >90% of cases are histologically classified as DLBCL. The present study reports the case of a 65-year-old female with CD20-negative PCNSL, whose primary clinical symptom was a persistent headache. Serum tests for human immunodeficiency virus, Epstein-Barr virus-DNA, human herpesvirus 8, hepatitis B and hepatitis C were negative. Cranial magnetic resonance imaging suggested multiple intracranial occupancies. The neoplastic cells were found to be positive for CD19, CD79α, Bcl-2 (~92%) and c-Myc (~50%), while showing negative results for CD20, CD138, programmed cell death protein 1 (PD-1) and programmed cell death receptor 1 ligand 1 (PD-L1). The Ki-67 proliferation index was >80%. In the tumor microenvironment, <10% of the tumor-associated macrophages expressed PD-L1. The number of PD-1-positive tumor-infiltrating lymphocytes was 30-40 cells according to high-power field microscopy. The patient's disease progressed during methotrexate-based treatment, leading to a change in the treatment regimen to the Bruton tyrosine kinase inhibitor, zanubrutinib, combined with the anti-PD-1 monoclonal antibody tislelizumab. After two courses of the combined treatment, the patient achieved complete remission (CR) and continued to receive consolidation treatment. In the 20 months of follow-up since CR was achieved, the patient's general condition was good and the disease was in continuous remission. The present case report and literature review show that a combination of drugs targeting different mechanisms may be used to treat PCNSL to prolong patient survival time. The mechanism of the enhanced efficacy of a combination of the two drugs may be related to the enhancement of antitumor T-cell immune responses and reversal of T-cell immune metabolic dysfunctions by the inhibition of glycolysis.

Project description: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 (??=?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.

Dataset Information

PD-L1 Monoclonal Antibody Treats Ischemic Stroke by Controlling Central Nervous System Inflammation.

Publications

PD-L1 Monoclonal Antibody Treats Ischemic Stroke by Controlling Central Nervous System Inflammation.

Similar Datasets

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