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Clinicopathological evaluation of PD-L1 expression and cytotoxic T-lymphocyte infiltrates across intracranial molecular subgroups of ependymomas: are these tumors potential candidates for immune check-point blockade?

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Abstract

Immune check-point blockade (ICB) targeting programmed cell death ligand-1 (PD-L1)/programmed death-1 (PD-1) axis has created paradigm shift in cancer treatment. ‘ST-RELA’ and ‘PF-A’ molecular subgroups of ependymomas (EPN) show poor outcomes. We aimed to understand the potential candidature of EPNs for ICB. Supratentorial (ST) Grade II/III EPNs were classified into ST-RELA, ST-YAP, and ST-not otherwise specified (NOS), based on RELA/YAP1 fusion transcripts and/or L1CAM and p65 protein expression. Posterior fossa (PF) EPNs were classified into PF-A and PF-B based on H3K27me3 expression. Immunohistochemistry for PD-L1 and CD8 was performed. RelA protein enrichment at PDL1 promoter site was analysed by chromatin immunoprecipitation-qPCR (ChIP-qPCR). Eighty-three intracranial EPNs were studied. Median tumor infiltrating CD8 + cytotoxic T-lymphocyte (CTL) density was 6/mm2, and was higher in ST-EPNs (median 10/mm2) as compared to PF-EPNs (median 3/mm2). PD-L1 expression was noted in 17/83 (20%) EPNs, including 12/31 ST-RELA and rare ST-NOS (2/12), PF-A (2/25) and PF-B (1/13) EPNs. Twelve EPNs (14%) showed high CTL density and concurrent PD-L1 positivity, of which majority (10/12) were ST-RELA EPNs. Enrichment of RelA protein was seen at PDL1 promoter. Increased CTL densities and upregulation of PD-L1 in ST-RELA ependymomas suggests potential candidature for immunotherapy.

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Funding

This work is supported by the Science and Engineering Research Board (SERB) (EMR/2016/003365), New Delhi, India; Central Institute of Industrial research (CSIR), New Delhi, India (Pool No 8948A/17); and Neurosciences centre, AIIMS, New Delhi (intramural grants).

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Author notes

  1. Aruna Nambirajan and Prit Benny Malgulwar are co-first authors.

Authors and Affiliations

  1. Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India

    Aruna Nambirajan, Prit Benny Malgulwar, Agrima Sharma, Vaishali Suri, Chitra Sarkar & Mehar Chand Sharma

  2. Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, 110029, India

    Meher Thej Boorgula, Ramesh Doddamani & Manmohan Singh

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  1. Aruna Nambirajan
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  2. Prit Benny Malgulwar
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Contributions

NA: conceptualization, methodology, formal analysis, data curation, writing—original draft, and writing—review and editing; MPB: methodology, data curation, formal analysis, writing—review and editing; SA: data curation, writing—review and editing; BM: data curation, writing—review and editing; SM: data curation, writing—review and editing; SV: data curation, writing—review and editing; SC: data curation, writing—review and editing; SMC: conceptualization, methodology, funding acquisition, project administration, formal analysis, data curation, writing—original draft, and writing—review and editing

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Correspondence to Mehar Chand Sharma.

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The research has been ethically approved by the institute ethics committee (Ref. No. IEC-602/03.11.2017)

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Nambirajan, A., Malgulwar, P.B., Sharma, A. et al. Clinicopathological evaluation of PD-L1 expression and cytotoxic T-lymphocyte infiltrates across intracranial molecular subgroups of ependymomas: are these tumors potential candidates for immune check-point blockade?. Brain Tumor Pathol 36, 152–161 (2019). https://doi.org/10.1007/s10014-019-00350-1

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