High levels of the soluble programmed death-ligand (sPD-L1) identify hepatocellular carcinoma patients with a poor prognosis

Finkelmeier, Fabian; Canli, Özge; Tal, Andrea O.; Pleli, Thomas; Trojan, Jörg; Schmidt, M; Kronenberger, Bernd; Zeuzem, Stefan; Piiper, Albrecht; Greten, Florian R.; Waidmann, Oliver

doi:10.1016/j.ejca.2016.03.002

Cited by 184 publications

(157 citation statements)

References 37 publications

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“…14,16 Accordingly, very high serum levels of sPD-1 and sPD-L1 were only observed in patients with elevated CRP levels in our study population (with a similar trend for higher mean sPD-1 and sPD-L1 levels in patients with elevated CRP). Importantly, serum levels of soluble PD-L1 were markedly elevated in (a subset of) patients with strong tumoral CD3C T cell infiltration.…”

Section: Discussionsupporting

confidence: 73%

“…11,23 Serum levels of sPD-1 and sPD-L1 have been reported to be independent prognostic factors in different solid tumors susceptible to immunotherapy targeting the PD-1 axis. 13,14,24 Regulation, provenience and function of the soluble forms of PD-1 and PD-L1 in cancer are still under discussion. 24 This is the first study to examine serum levels of sPD-1 and sPD-L1 in advanced PC.…”

Section: Discussionmentioning

confidence: 99%

“…In other cancer entities, different approaches to determine prognostic cut-off values have been used: median sPD-L1 serum level in the analyzed cancer patient cohort, sPD-L1 serum levels in a corresponding cohort of healthy individuals or receiver operating characteristic (ROC) curve models to define an ideal prognostic cut-off value. [14][15][16][17][18] In all aforementioned studies, the prognostic cut-off value was in the range of the 50th (i.e., median) and 75th percentile of the observed sPD-L1 levels in the whole analyzed patient cohort. When designing our study we therefore decided to use the median and the 75th percentile of sPD-1 and sPD-L1 levels observed in our study to define a cohort of patients with high versus low levels of the two molecules.…”

Section: Spd-1 and Spd-l1 Elisasmentioning

confidence: 99%

“…[10][11][12] High levels of soluble plasma PD-L1 (sPD-L1) were described as an adverse prognostic factor in several malignancies susceptible to PD-1/PD-L1 blockade, including renal cell cancer and hepatocellular carcinoma (HCC). 13,14 To date, provenience, regulation and immunologic function of sPD-1 and sPD-L1 in cancer remain uncertain. Plasma levels of sPD-1 and sPD- L1 have not yet been determined conjointly in any cancer type.…”

Section: Introductionmentioning

confidence: 99%

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Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer

et al. 2017

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Up to now, the efficacy of programmed death protein 1/programmed death ligand 1 (PD-1/PD-L1) blockade in pancreatic cancer (PC) remains uncertain. Serum levels of soluble PD-1 and PD-L1 (sPD-1/sPD-L1) have been reported to be independent prognostic factors in solid tumors susceptible to checkpoint blockade. Provenience, regulation and immunologic function of sPD-1 and sPD-L1 in cancer are poorly understood. To the best of our knowledge, sPD-1 and sPD-L1 have not been measured conjointly in any cancer type yet.In contrast to other tumor entities, sPD-1/sPD-L1 levels did not indicate an adverse outcome in a cohort of 41 patients with advanced PC. We observed a close positive correlation of sPD-L1 levels with sPD-1 in patients with advanced PC, suggesting a common provenience and regulation of sPD-1 and sPD-L1 in cancer patients. Higher sPD-L1 levels were present in patients with elevated C-reactive protein or strong tumoral T cell infiltration, while no correlation of sPD-L1 levels with tumoral PD-L1 expression was found. Our findings indicate that sPD-1 and sPD-L1 are markers of systemic inflammation in (pancreatic) cancer. In a subset of PC patients, elevation in sPD-L1 levels might be caused by an inflammatory tumor typeindependent of tumoral PD-L1 expression.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Spd-1 and Spd-l1 Elisasmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer

et al. 2017

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“…One additional immune-evasion strategy to take into account is correlated with the expression and/or secretion of an immune checkpoint molecule, such as the PD-L1 molecule by AML cells [32] [33] [34]. In our in vitro co-culture experiments we observed cytotoxic activity from CAR T-cells challenged with either PD-L1 neg or PD-L1 + AML blasts, although it is possible that in the in vivo milieu , this mechanism could contribute to increased T-cell apoptosis for binding the respective receptor on T-cells, as PD-1 + CD8 T-cells were found to increase in AML metastatic site in vivo [35].…”

Section: Discussionmentioning

confidence: 99%

In Vitro Pre-Clinical Validation of Suicide Gene Modified Anti-CD33 Redirected Chimeric Antigen Receptor T-Cells for Acute Myeloid Leukemia

Minagawa¹,

Jamil²,

Al‐Obaidi³

et al. 2016

PLoS ONE

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BackgroundApproximately fifty percent of patients with acute myeloid leukemia can be cured with current therapeutic strategies which include, standard dose chemotherapy for patients at standard risk of relapse as assessed by cytogenetic and molecular analysis, or high-dose chemotherapy with allogeneic hematopoietic stem cell transplant for high-risk patients. Despite allogeneic hematopoietic stem cell transplant about 25% of patients still succumb to disease relapse, therefore, novel strategies are needed to improve the outcome of patients with acute myeloid leukemia.Methods and findingsWe developed an immunotherapeutic strategy targeting the CD33 myeloid antigen, expressed in ~ 85–90% of patients with acute myeloid leukemia, using chimeric antigen receptor redirected T-cells. Considering that administration of CAR T-cells has been associated with cytokine release syndrome and other potential off-tumor effects in patients, safety measures were here investigated and reported. We genetically modified human activated T-cells from healthy donors or patients with acute myeloid leukemia with retroviral supernatant encoding the inducible Caspase9 suicide gene, a ΔCD19 selectable marker, and a humanized third generation chimeric antigen receptor recognizing human CD33. ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells had a 75±3.8% (average ± standard error of the mean) chimeric antigen receptor expression, were able to specifically lyse CD33+ targets in vitro, including freshly isolated leukemic blasts from patients, produce significant amount of tumor-necrosis-factor-alpha and interferon-gamma, express the CD107a degranulation marker, and proliferate upon antigen specific stimulation. Challenging ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells with programmed-death-ligand-1 enriched leukemia blasts resulted in significant killing like observed for the programmed-death-ligand-1 negative leukemic blasts fraction. Since the administration of 10 nanomolar of a non-therapeutic dimerizer to activate the suicide gene resulted in the elimination of only 76.4±2.0% gene modified cells in vitro, we found that co-administration of the dimerizer with either the BCL-2 inhibitor ABT-199, the pan-BCL inhibitor ABT-737, or mafosfamide, resulted in an additive effect up to complete cell elimination.ConclusionsThis strategy could be investigated for the safety of CAR T-cell applications, and targeting CD33 could be used as a ‘bridge” therapy for patients coming to allogeneic hematopoietic stem cell transplant, as anti-leukemia activity from infusing CAR.CD33 T-cells has been demonstrated in an ongoing clinical trial. Albeit never performed in the clinical setting, our future plan is to investigate the utility of iC9-CAR.CD33 T-cells as part of the conditioning therapy for an allogeneic hematopoietic stem cell transplant for acute myeloid leukemia, together with other myelosuppressive agents, whilst the activation of the inducible Caspase9 suicide gene would grant elimination of the infused gene modified T-cells prior to stem cell inf...

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High serum PD‐L1 level is a poor prognostic biomarker in surgically treated esophageal cancer

et al. 2019

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Background Programmed death ligand 1 (PD‐L1) inhibitor has been approved as one of the standard therapies for various cancers. Some reports have shown that serum PD‐L1 level is associated with advanced tumor stages and poor prognosis; however, corresponding pathological information in esophageal cancer patients is lacking. Therefore, we evaluated the clinicopathological and prognostic impact of serum PD‐L1 levels in surgically treated esophageal cancer. Methods A total of 150 patients who underwent radical resection for esophageal cancer were included in the study. Preoperative serum PD‐L1 levels were analyzed using the enzyme‐linked immunosorbent assay kit. A cutoff level of 65.6 pg/mL was used to divide the patients into two groups, and univariate and multivariate analyses were conducted to compare the clinicopathological characteristics and prognoses between these two groups. Results Although significant associations between serum PD‐L1 levels and clinicopathological variables were observed, serum PD‐L1 level was significantly associated with high neutrophil counts, high CRP levels, low albumin levels, and high squamous cell carcinoma antigen levels. Furthermore, serum PD‐L1 level was associated with poor overall survival independent to TNM factors. Conclusions High preoperative level of serum PD‐L1 is a prognostic factor for poor overall survival in patients with surgically treated esophageal cancer.

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High levels of the soluble programmed death-ligand (sPD-L1) identify hepatocellular carcinoma patients with a poor prognosis

Cited by 184 publications

References 37 publications

Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer

Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer

In Vitro Pre-Clinical Validation of Suicide Gene Modified Anti-CD33 Redirected Chimeric Antigen Receptor T-Cells for Acute Myeloid Leukemia

High serum PD‐L1 level is a poor prognostic biomarker in surgically treated esophageal cancer

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