Soluble programmed death-ligand 1 as a prognostic biomarker for overall survival in patients with diffuse large B-cell lymphoma: a replication study and combined analysis of 508 patients

Rossille, Delphine; Azzaoui, Imane; Feldman, Andrew L.; Maurer, Matthew J.; Labouré, Gaëlle; Parrens, Marie; Pangault, Céline; Habermann, Thomas M.; Ansell, Stephen M.; Link, Brian K.; Tarte, Karin; Witzig, Thomas E.; Lamy, Thierry; Slager, Susan L.; Roussel, Mikaël; Milpied, Noël; Cerhan, James R.; Fest, Thierry

doi:10.1038/leu.2016.385

Cited by 44 publications

(28 citation statements)

References 15 publications

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“…Depending on the cut‐off levels used for positivity, previous studies on adult DLBCL indicated a wide range of 26%‐75% of patients to be PD‐L1‐positive . In studies including immunocompromised patients, similar to our patient cohort, the proportion of PD‐L1‐positive B‐cell lymphoma cases was rather comparable to that seen by us .…”

Section: Discussionsupporting

confidence: 88%

PD‐L1 and PD1 expression in post‐transplantation lymphoproliferative disease (PTLD) of childhood and adolescence: An inter‐ and intra‐individual descriptive study covering the whole spectrum of PTLD categories

et al. 2019

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Therapy of children with post‐transplantation lymphoproliferative disorder (PTLD) after hematopoietic stem cell (HSCT) and solid organ transplantation (SOT) can be challenging. In this retrospective study, we investigated PD‐L1 and PD1 expression in all PTLD categories of childhood and adolescence to see whether checkpoint inhibition with PD‐L1/PD1 inhibitors may serve as a therapy option. We included 21 patients aged 19 years or younger (at date of transplant) with PTLD following SOT or HSCT having adequate tumor samples available (n = 29). Using immunohistochemistry, we evaluated PD‐L1/PD1 expression on both tumor cells and cells of the microenvironment in all samples. Availability of consecutively matched tumor samples during 6 of 21 patients' disease courses also allowed an intra‐individual assessment of PD‐L1/PD1 expression. We observed lower PD‐L1 and higher PD1 expression in non‐destructive lesions, and higher PD‐L1 and lower PD1 expression in polymorphic and, in particular, in monomorphic PTLD, mostly diffuse large B‐cell lymphomas (DLBCL, n = 10/21). The amount of PD‐L1‐ and PD1‐positive cells changed in the opposite way in sequential biopsies of the same individual correlating well with the PTLD category. This is the first comprehensive pediatric study assessing PD‐L1 and PD1 expression on tumor cells and in the microenvironment of PTLD including not only monomorphic, but also non‐destructive early lesions. PD‐L1 expression of the tumor cells inversely correlated with PD1 expression in surrounding tissues, with the highest expression in DLBCL. Since PTLD can be therapeutically challenging, our results indicate a potential efficacy of checkpoint inhibitors if standard immune‐ and/or chemotherapy fail or are impossible. We therefore recommend routine staining of PD‐L1 and PD1 in all PTLD categories.

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Section: Discussionsupporting

confidence: 88%

PD‐L1 and PD1 expression in post‐transplantation lymphoproliferative disease (PTLD) of childhood and adolescence: An inter‐ and intra‐individual descriptive study covering the whole spectrum of PTLD categories

et al. 2019

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“…In previous studies, high level of soluble PD-L1 in blood was an independent poor prognostic factor for OS in patients with systemic DLBCL. 36 Given the poor prognostic implication of tPD-L1 in PCNS-DLBCL observed in this study, it may deserve to investigate the prognostic significance of soluble PD-L1 in blood or cerebrospinal fluid in PCNS-DLBCL.…”

Section: Pd-1 Expression Is Induced By T-cell Receptor Signaling On Amentioning

confidence: 89%

High tumoral PD-L1 expression and low PD-1⁺ or CD8⁺ tumor-infiltrating lymphocytes are predictive of a poor prognosis in primary diffuse large B-cell lymphoma of the central nervous system

et al. 2019

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We investigated the clinicopathological role of the PD-1/PD-L1 pathway in primary diffuse large B-cell lymphoma of the central nervous system (PCNS-DLBCL) arising in the immune-privileged site. PD-L1 immunostaining of ≥30% of tumor cells was defined as tPD-L1+, and PD-L1 immunostaining of ≥30% of total cellularity, including tumor and non-tumoral cells, as tmPD-L1+ . PD-1 + and CD8 + tumor-infiltrating lymphocytes (TILs) were enumerated. Thirty-five cases (35.7%) were tPD-L1+ and 47 cases (48%) were tmPD-L1+ . The number of TILs was greater in tmPD-L1+ cases than in tmPD-L1− cases (CD8 + , P= .050; PD-1 + , P= .019). tPD-L1+ and tmPD-L1+ cases tended to have a poor performance status. In contrast, the numbers of CD8 + and PD-1 + TILs tended to be higher in patients with a good performance status and MYC/BCL2 negativity. Patients with tPD-L1+ had a worse overall survival (P= .026), and those with increased CD8 + or PD-1 + TILs tended to have a better overall survival (P= .081 and 0.044, respectively). Tumoral PD-L1 expression and the number of PD-1 + TILs were independent prognostic factors. tPD-L1+ patients with a small number of CD8 + or PD-1 + TILs had the worst prognosis, and tPD-L1− patients with a large number of CD8 + or PD-1 + TILs had the best prognosis. In validation group, increased CD8 + or PD-1 + TILs were significantly associated with a prolonged survival, but PD-L1 had no prognostic significance. In conclusion, PD-L1 is frequently expressed in tumor cells and the immune microenvironment of PCNS-DLBCL and is correlated with increased TILs. PD-L1 and CD8 + and PD-1 + TILs have potential as prognostic biomarkers and therapeutic targets in PCNS-DLBCL. ARTICLE HISTORY

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“…Moreover, a soluble form of PD-L1 was detected in the plasma but not in the serum of peripheral blood from DLBCL patients, and its expression levels had no correlation with PD-L1 expression on tumors. Elevated soluble PD-L1 expression was found to be either associated 89,90 or not associated 95 with poorer prognosis.…”

Section: Pd-l1 Expression and Clinical Roles In B-cell Lymphomasmentioning

confidence: 95%

“…25,41,87 PD-L1 was shown to be expressed in 26% to 75% of DLBCL samples with PD-L1 1 cutoff $5% 61,87-89 and more frequently in ABC-DLBCL, 57,60,87,88 and tumor PD-L1 expression has been associated with either poor prognosis or no significant prognostic effect. 57,58,61,90 PDL1/ PDL2 amplifications are rare in DLBCL, and 9p24.1 copy gain was identified in only 6% to 19% of patients with DLBCL. 57,88,91 Another form of genetic alteration, disruption of the PDL1 39 untranslated region, was identified in 8% of DLBCL samples.…”

Section: Pd-l1 Expression and Clinical Roles In B-cell Lymphomasmentioning

confidence: 99%

PD-1 expression and clinical PD-1 blockade in B-cell lymphomas

Xu-Monette

Zhou

Young

2018

Blood

340

306

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Programmed cell death protein 1 (PD-1) blockade targeting the PD-1 immune checkpoint has demonstrated unprecedented clinical efficacy in the treatment of advanced cancers including hematologic malignancies. This article reviews the landscape of PD-1/programmed death-ligand 1 (PD-L1) expression and current PD-1 blockade immunotherapy trials in B-cell lymphomas. Most notably, in relapsed/refractory classical Hodgkin lymphoma, which frequently has increased PD-1 tumor-infiltrating T cells, 9p24.1 genetic alteration, and high PD-L1 expression, anti-PD-1 monotherapy has demonstrated remarkable objective response rates (ORRs) of 65% to 87% and durable disease control in phase 1/2 clinical trials. The median duration of response was 16 months in a phase 2 trial. PD-1 blockade has also shown promise in a phase 1 trial of nivolumab in relapsed/refractory B-cell non-Hodgkin lymphomas, including follicular lymphoma, which often displays abundant PD-1 expression on intratumoral T cells, and diffuse large B-cell lymphoma, which variably expresses PD-1 and PD-L1. In primary mediastinal large B-cell lymphoma, which frequently has 9p24.1 alterations, the ORR was 35% in a phase 2 trial of pembrolizumab. In contrast, the ORR with pembrolizumab was 0% in relapsed chronic lymphocytic leukemia (CLL) and 44% in CLL with Richter transformation in a phase 2 trial. T cells from CLL patients have elevated PD-1 expression; CLL PD-1 T cells can exhibit a pseudo-exhaustion or a replicative senescence phenotype. PD-1 expression was also found in marginal zone lymphoma but not in mantle cell lymphoma, although currently anti-PD-1 clinical trial data are not available. Mechanisms and predictive biomarkers for PD-1 blockade immunotherapy, treatment-related adverse events, hyperprogression, and combination therapies are discussed in the context of B-cell lymphomas.

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Soluble programmed death-ligand 1 as a prognostic biomarker for overall survival in patients with diffuse large B-cell lymphoma: a replication study and combined analysis of 508 patients

Cited by 44 publications

References 15 publications

PD‐L1 and PD1 expression in post‐transplantation lymphoproliferative disease (PTLD) of childhood and adolescence: An inter‐ and intra‐individual descriptive study covering the whole spectrum of PTLD categories

PD‐L1 and PD1 expression in post‐transplantation lymphoproliferative disease (PTLD) of childhood and adolescence: An inter‐ and intra‐individual descriptive study covering the whole spectrum of PTLD categories

High tumoral PD-L1 expression and low PD-1⁺ or CD8⁺ tumor-infiltrating lymphocytes are predictive of a poor prognosis in primary diffuse large B-cell lymphoma of the central nervous system

PD-1 expression and clinical PD-1 blockade in B-cell lymphomas

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Soluble programmed death-ligand 1 as a prognostic biomarker for overall survival in patients with diffuse large B-cell lymphoma: a replication study and combined analysis of 508 patients

Cited by 44 publications

References 15 publications

PD‐L1 and PD1 expression in post‐transplantation lymphoproliferative disease (PTLD) of childhood and adolescence: An inter‐ and intra‐individual descriptive study covering the whole spectrum of PTLD categories

PD‐L1 and PD1 expression in post‐transplantation lymphoproliferative disease (PTLD) of childhood and adolescence: An inter‐ and intra‐individual descriptive study covering the whole spectrum of PTLD categories

High tumoral PD-L1 expression and low PD-1+ or CD8+ tumor-infiltrating lymphocytes are predictive of a poor prognosis in primary diffuse large B-cell lymphoma of the central nervous system

PD-1 expression and clinical PD-1 blockade in B-cell lymphomas

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High tumoral PD-L1 expression and low PD-1⁺ or CD8⁺ tumor-infiltrating lymphocytes are predictive of a poor prognosis in primary diffuse large B-cell lymphoma of the central nervous system