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Immunophenotyping of the PD-L1-positive cells in angioimmunoblastic T cell lymphoma and Hodgkin disease.

ABSTRACT: OBJECTIVE:Programmed death-1 (PD-1) and its ligand PD-L1 are now used as predictive biomarkers to guide clinical decisions. Precise characterization of PD-L1-positive cells may contribute to our knowledge of which patients derive benefit from the PD-L1 blockade therapy. RESULTS:To address this issue, we performed immunophenotyping of PD-L1-positive cells in Hodgkin lymphoma and in angioimmunoblastic T cell lymphoma (AITL) employing multiple immunofluorescent immunolabeling. We found that PD-L1-positive cells and PD-1-positive cells both in Hodgkin lymphoma and in AITL belong to two completely different cell lineages. In both lymphomas, PD-1 was found exclusively in T-lymphocytes, whereas PD-L1 was revealed in the tumor microenvironment cells including macrophages. PD-L1 was also detected in CD30-positive cells in Hodgkin lymphoma but not in AITL. The marker of B-cell lineage, CD20, was not detectable in PD-L1-positive cells both in AITL and in Hodgkin. Our study highlights the importance of comprehensive assessment of PD-1/PD-L1 regulatory pathways for employing PD-L1 as a predictive biomarker in clinical practice. PD-L1-antibody therapy is proven in Hodgkin lymphoma. Comparative immunophenotyping of the PD-1/PD-L1 axis provides a support for attempts to prove this principle also for AITL.

SUBMITTER: Tiemann M

PROVIDER: S-EPMC7060537 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Immunophenotyping of the PD-L1-positive cells in angioimmunoblastic T cell lymphoma and Hodgkin disease.

Tiemann Markus M Samoilova Vera V Atiakshin Dmitri D Buchwalow Igor I

BMC research notes 20200307 1

<h4>Objective</h4>Programmed death-1 (PD-1) and its ligand PD-L1 are now used as predictive biomarkers to guide clinical decisions. Precise characterization of PD-L1-positive cells may contribute to our knowledge of which patients derive benefit from the PD-L1 blockade therapy.<h4>Results</h4>To address this issue, we performed immunophenotyping of PD-L1-positive cells in Hodgkin lymphoma and in angioimmunoblastic T cell lymphoma (AITL) employing multiple immunofluorescent immunolabeling. We fou ...[more]

PMID: 32143684

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Project description:Classical Hodgkin lymphomas (cHLs) include small numbers of malignant Reed-Sternberg cells within an extensive but ineffective inflammatory/immune cell infiltrate. In cHL, chromosome 9p24.1/PD-L1/PD-L2 alterations increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and their further induction through Janus kinase 2-signal transducers and activators of transcription signaling. The unique composition of cHL limits its analysis with high-throughput genomic assays. Therefore, the precise incidence, nature, and prognostic significance of PD-L1/PD-L2 alterations in cHL remain undefined.We used a fluorescent in situ hybridization assay to evaluate CD274/PD-L1 and PDCD1LG2/PD-L2 alterations in 108 biopsy specimens from patients with newly diagnosed cHL who were treated with the Stanford V regimen and had long-term follow-up. In each case, the frequency and magnitude of 9p24.1 alterations-polysomy, copy gain, and amplification-were determined, and the expression of PD-L1 and PD-L2 was evaluated by immunohistochemistry. We also assessed the association of 9p24.1 alterations with clinical parameters, which included stage (early stage I/II favorable risk, early stage unfavorable risk, advanced stage [AS] III/IV) and progression-free survival (PFS).Ninety-seven percent of all evaluated cHLs had concordant alterations of the PD-L1 and PD-L2 loci (polysomy, 5% [five of 108]; copy gain, 56% [61 of 108]; amplification, 36% [39 of 108]). There was an association between PD-L1 protein expression and relative genetic alterations in this series. PFS was significantly shorter for patients with 9p24.1 amplification, and the incidence of 9p24.1 amplification was increased in patients with AS cHL.PD-L1/PD-L2 alterations are a defining feature of cHL. Amplification of 9p24.1 is more common in patients with AS disease and associated with shorter PFS in this series. Further analyses of 9p24.1 alterations in patients treated with standard cHL induction regimens or checkpoint blockade are warranted.

Project description:Much focus has been on the interaction of programmed cell death ligand 1 (PD-L1) on malignant B cells with programmed cell death 1 (PD-1) on effector T cells in inhibiting antilymphoma immunity. We sought to establish the contribution of natural killer (NK) cells and inhibitory CD163+ monocytes/macrophages in Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL). Levels of PD-1 on NK cells were elevated in cHL relative to DLBCL. Notably, CD3-CD56hiCD16-ve NK cells had substantially higher PD-1 expression relative to CD3-CD56dimCD16+ cells and were expanded in blood and tissue, more marked in patients with cHL than patients with DLBCL. There was also a raised population of PD-L1-expressing CD163+ monocytes that was more marked in patients with cHL compared with patients with DLBCL. The phenotype of NK cells and monocytes reverted back to normal once therapy (ABVD [doxorubicin 25 mg/m2, bleomycin 10 000 IU/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2, all given days 1 and 15, repeated every 28 days] or R-CHOP [rituximab 375 mg/m2, cyclophosphamide 750 mg/m2 IV, doxorubicin 50 mg/m2 IV, vincristine 1.4 mg/m2 (2 mg maximum) IV, prednisone 100 mg/day by mouth days 1-5, pegfilgrastim 6 mg subcutaneously day 4, on a 14-day cycle]) had commenced. Tumor-associated macrophages (TAMs) expressed high levels of PD-L1/PD-L2 within diseased lymph nodes. Consistent with this, CD163/PD-L1/PD-L2 gene expression was also elevated in cHL relative to DLBCL tissues. An in vitro functional model of TAM-like monocytes suppressed activation of PD-1hi NK cells, which was reversed by PD-1 blockade. In line with these findings, depletion of circulating monocytes from the blood of pretherapy patients with cHL and patients with DLBCL enhanced CD3-CD56hiCD16-ve NK-cell activation. We describe a hitherto unrecognized immune evasion strategy mediated via skewing toward an exhausted PD-1-enriched CD3-CD56hiCD16-ve NK-cell phenotype. In addition to direct inhibition of NK cells by the malignant B cell, suppression of NK cells can occur indirectly by PD-L1/PD-L2-expressing TAMs. The mechanism is more prominent in cHL than DLBCL, which may contribute to the clinical sensitivity of cHL to PD-1 blockade.

Dataset Information

Immunophenotyping of the PD-L1-positive cells in angioimmunoblastic T cell lymphoma and Hodgkin disease.

Publications

Immunophenotyping of the PD-L1-positive cells in angioimmunoblastic T cell lymphoma and Hodgkin disease.

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