Specific expression of PD‐L1 in RELA‐fusion supratentorial ependymoma: Implications for PD‐1‐targeted therapy

Witt, Davis; Donson, Andrew M.; Amani, Vladimir; Moreira, Daniel C.; Sanford, Bridget; Hoffman, Lindsey M.; Handler, Michael H.; Levy, Jean M. Mulcahy; Jones, Kenneth L.; Nellan, Anandani; Foreman, Nicholas K.; Griesinger, Andrea

doi:10.1002/pbc.26960

Cited by 47 publications

(33 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Again, as previously mentioned, such a finding far from guarantees a response and in these landmark papers they found that even in patients that expressed PD-L1 on tumor cells, the response rate to the treatment was only 39% [44]. In addition, Witt et al [46] nicely demonstrated, using T cell exhaustion testing of various types of ependymomas, that elevated PD-L1 expression in tumors can be indicative of either tumor adaptations to hide from the innate immune response or due to normal T-cell antigen-activation, a known function of PD-1. In their study they utilized functional T cell exhaustion assays that stimulate T cells via exposure to Phorbol 12-myristate 13-acetate (PMA)/ionomycin.…”

Section: Immune Checkpoint Inhibitors and Their Potential Use In Acpmentioning

confidence: 89%

“…They found that infiltrating T-cells in RELA fusion supratentorial ependymoma did not secrete IFN-gamma. They concluded that this suggested that in the case of RELA fusion ependymoma, the increased expression of PD-1/PD-L1 results in the exhaustion of infiltrating T-cells and immune evasion by the tumor [46]. On the contrary, they found that in group B ependymomas (which also express high levels of PD-1), infiltrating T-cells were, in fact, capable of secreting IFN-gamma after stimulation with PMA/ionomycin.…”

Section: Immune Checkpoint Inhibitors and Their Potential Use In Acpmentioning

confidence: 99%

“…On the contrary, they found that in group B ependymomas (which also express high levels of PD-1), infiltrating T-cells were, in fact, capable of secreting IFN-gamma after stimulation with PMA/ionomycin. They posited that in these tumors, elevated expression of PD-1 was representative of normal T-cell activation in response to the tumor [46]. As such, although the findings by Coy et al [33] of elevated PD-1/PD-L1 expression in ACP are exciting and may result in an alternative treatment strategy in resistant and multiply recurrent cases, further investigation is necessary to fully elucidate the implications of this increased PD-1/PD-L1 expression in ACP before any widespread implementation.…”

Section: Immune Checkpoint Inhibitors and Their Potential Use In Acpmentioning

confidence: 99%

See 2 more Smart Citations

The Inflammatory Milieu of Adamantinomatous Craniopharyngioma and Its Implications for Treatment

Whelan

Prince

Gilani

et al. 2020

JCM

View full text Add to dashboard Cite

Pediatric Adamantinomatous Craniopharyngiomas (ACPs) are histologically benign brain tumors that often follow an aggressive clinical course. Their suprasellar location leaves them in close proximity to critical neurological and vascular structures and often results in significant neuroendocrine morbidity. Current treatment paradigms, involving surgical resection and radiotherapy, confer significant morbidity to patients and there is an obvious need to discover effective and safe alternative treatments. Recent years have witnessed significant efforts to fully detail the genomic, transcriptomic and proteomic make-up of these tumors, in an attempt to identify potential therapeutic targets. These studies have resulted in ever mounting evidence that inflammatory processes and the immune response play a critical role in the pathogenesis of both the solid and cystic portion of ACPs. Several inflammatory and immune markers have been identified in both the cyst fluid and solid tumor tissue of ACP. Due to the existence of effective agents that target them, IL-6 and immune checkpoint inhibitors seem to present the most likely immediate candidates for clinical trials of targeted immune-related therapy in ACP. If effective, such agents may result in a paradigm shift in treatment that ultimately reduces morbidity and results in better outcomes for our patients.

show abstract

Section: Immune Checkpoint Inhibitors and Their Potential Use In Acpmentioning

confidence: 89%

Section: Immune Checkpoint Inhibitors and Their Potential Use In Acpmentioning

confidence: 99%

Section: Immune Checkpoint Inhibitors and Their Potential Use In Acpmentioning

confidence: 99%

See 1 more Smart Citation

The Inflammatory Milieu of Adamantinomatous Craniopharyngioma and Its Implications for Treatment

Whelan

Prince

Gilani

et al. 2020

JCM

View full text Add to dashboard Cite

show abstract

“…However, PD-1/PD-L1 axis influence the balance between tumor immune surveillance and immune resistance as well [ 12 , 13 ]. Elevated PD-L1 expression on tumor cell or tumor infiltrating lymphocyte (TIL) results in the exhaustion of T cell [ 14 ], thus the attenuated tumor-specific immunity promoting tumor progression [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors

et al. 2018

View full text Add to dashboard Cite

Programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) is a negative modulatory signaling pathway for activation of T cell. It is acknowledged that PD-1/PD-L1 axis plays a crucial role in the progression of tumor by altering status of immune surveillance. As one of the most promising immune therapy strategies, PD-1/PD-L1 inhibitor is a breakthrough for the therapy of some refractory tumors. However, response rate of PD-1/PD-L1 inhibitors in overall patients is unsatisfactory, which limits the application in clinical practice. Therefore, biomarkers which could effectively predict the efficacy of PD-1/PD-L1 inhibitors are crucial for patient selection. Biomarkers reflecting tumor immune microenvironment and tumor cell intrinsic features, such as PD-L1 expression, density of tumor infiltrating lymphocyte (TIL), tumor mutational burden, and mismatch-repair (MMR) deficiency, have been noticed to associate with treatment effect of anti-PD-1/anti-PD-L1 therapy. Furthermore, gut microbiota, circulating biomarkers, and patient previous history have been found as valuable predictors as well. Therefore establishing a comprehensive assessment framework involving multiple biomarkers would be meaningful to interrogate tumor immune landscape and select sensitive patients.

show abstract

“…An oncogenic fusion of RELA with C11orf95 has been described in the majority of supratentorially located ependymoma, and supratentorial RELA ‐fused ependymoma (ST‐EPN‐RELA) was introduced as a separate entity in the 2016 World Health Organization (WHO) classification of CNS tumors . Although preclinical evidence exists on subgroup specific potential drugs, data on the clinical impact of the molecular diagnosis are rare and refer to heterogeneous, retrospective cohorts, with limited information on clinical staging and treatment . Previously described markers for risk association are gain of 1q, which was associated with poor prognosis in several cohorts, whereas histopathological grading could not be confirmed as a clinical prognostic marker .…”

Section: Introductionmentioning

confidence: 99%

Newly Diagnosed Metastatic Intracranial Ependymoma in Children: Frequency, Molecular Characteristics, Treatment, and Outcome in the Prospective HIT Series

et al. 2019

View full text Add to dashboard Cite

Background Data on frequency, clinical presentation, and outcome of primary metastatic intracranial ependymoma in children are scarce. Patients and Methods Prospective data on patients younger than 21 years with metastatic intracranial ependymoma at first diagnosis, registered from 2001 to 2014 in the HIT‐2000 trial and the HIT‐2000 Interim Registry, were analyzed. Results Of 453 registered patients with intracranial ependymoma and central neuropathology review, initial staging included spinal magnetic resonance imaging in all patients and lumbar cerebrospinal fluid (CSF) analysis in 402 patients. Ten patients (2.2%) had metastatic disease, including three with microscopic CSF positivity only (M1 metastasis stage, 0.7% of patients with CSF staging). Location of the primary tumor was supratentorial in four patients (all supratentorial RELA‐fused ependymoma [ST‐EPN‐RELA]) and within the posterior fossa in five patients (posterior fossa ependymoma type A [PF‐EPN‐A], n = 4; posterior fossa ependymoma not further classifiable, n = 1), and multifocal in one patient. All four patients with ST‐EPN‐RELA were alive in first or second complete remission (CR) 7.5–12.3 years after diagnosis. All four patients with macroscopic metastases of posterior fossa or multifocal ependymoma died. Three patients with initial M1 stage (ST‐EPN‐RELA, n = 1; PF‐EPN‐A, n = 2) received chemotherapy and local irradiation and were alive in second or third CR 3.0–9.7 years after diagnosis. Progression‐free and overall survival of the entire cohort at 5 years was 13% (±6%), and 58% (±16%), respectively. Conclusion Primary metastatic disease is rare in children with intracranial ependymoma. Prognosis may depend on molecular subgroup and extent of dissemination, and relevance of CSF analysis for initial staging remains to be clarified. Implications for Practice Childhood ependymoma presenting with metastasis at first diagnosis is very rare with a frequency of 2.4% in this population‐based, well‐characterized cohort. Detection of microscopic metastases in the cerebrospinal fluid was extremely rare, and impact on prognosis and respective treatment decision on irradiation field remains unclear. Initial metastatic presentation occurs in both supratentorial RELA‐fused ependymoma and posterior fossa ependymoma. Prognosis may differ according to extent of metastasis and biological subgroup, with poor prognosis in diffusely spread metastatic posterior fossa ependymoma even after combination therapy with both intensive chemotherapy and craniospinal irradiation, which may help to guide individual therapeutic decisions for future patients.

show abstract

Specific expression of PD‐L1 in RELA‐fusion supratentorial ependymoma: Implications for PD‐1‐targeted therapy

Abstract: These findings in ST-RELA suggest tumor evasion and immunsuppression due to PD-L1/PD-1-mediated T-cell exhaustion. Trials of checkpoint inhibitors in EPN should be enriched for ST-RELA tumors.

Cited by 47 publications

References 25 publications

The Inflammatory Milieu of Adamantinomatous Craniopharyngioma and Its Implications for Treatment

The Inflammatory Milieu of Adamantinomatous Craniopharyngioma and Its Implications for Treatment

Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors

Newly Diagnosed Metastatic Intracranial Ependymoma in Children: Frequency, Molecular Characteristics, Treatment, and Outcome in the Prospective HIT Series

Contact Info

Product

Resources

About