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Pediatric pan-central nervous system tumor analysis of immune-cell infiltration identifies correlates of antitumor immunity

Lookup NU author(s): Dr Yura Grabovska, Dr Stephen Crosier, Dr Martina Finetti, Dr Ed Schwalbe, Dr Rebecca Hill, Dr Janet Lindsey, Dr Debbie Hicks, Professor Simon BaileyORCiD, Professor Steven CliffordORCiD, Dr Daniel Williamson

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2020, The Author(s).Immune-therapy is an attractive alternative therapeutic approach for targeting central nervous system (CNS) tumors and the constituency of the Tumor Immune Microenvironment (TIME) likely to predict patient response. Here, we describe the TIME of >6000 primarily pediatric CNS tumors using a deconvolution approach (methylCIBERSORT). We produce and validate a custom reference signature defining 11 non-cancer cell types to estimate relative proportions of infiltration in a panCNS tumor cohort spanning 80 subtypes. We group patients into three broad immune clusters associated with CNS tumor types/subtypes. In cohorts of medulloblastomas (n = 2325), malignant rhabdoid tumors (n = 229) and pediatric high-grade gliomas (n = 401), we show significant associations with molecular subgroups/subtypes, mutations, and prognosis. We further identify tumor-specific immune clusters with phenotypic characteristics relevant to immunotherapy response (i.e. Cytolytic score, PDL1 expression). Our analysis provides an indication of the potential future therapeutic and prognostic possibilities of immuno-methylomic profiling in pediatric CNS tumor patients that may ultimately inform approach to immune-therapy.

Publication metadata

Author(s): Grabovska Y, Mackay A, O'Hare P, Crosier S, Finetti M, Schwalbe EC, Pickles JC, Fairchild AR, Avery A, Cockle J, Hill R, Lindsey J, Hicks D, Kristiansen M, Chalker J, Anderson J, Hargrave D, Jacques TS, Straathof K, Bailey S, Jones C, Clifford SC, Williamson D

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2020

Volume: 11

Issue: 1

Print publication date: 01/12/2020

Online publication date: 28/08/2020

Acceptance date: 24/07/2020

Date deposited: 26/11/2020

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41467-020-18070-y

DOI: 10.1038/s41467-020-18070-y

PubMed id: 32859926

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Funding

Funder referenceFunder name
... co-funded by The Brain Tumour Charity, Great Ormond Street Children’s Charity, and Children with Cancer UK (16/193).
A number of ATRT 850K methylation profiles were produced by and kindly contributed to the research study by UCL Genomics/SIHMDS-Acquired Genomics.
Action Medical Research, SPARKS, The JGW Patterson Foundation,
and the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London.
Cancer Research UK (C8464/A13457 & C8464/A2339),
Children’s Cancer and Leukaemia Group (CCLG) Biological Study 2012 BS 05 and as part of the INSTINCT network program grant ...
Funding support was provided by Love Oliver, CCLG Pilot Award, North of England Children’s Cancer Research, a Children with Cancer UK start-up grant (12-1234),
Star for Harris,
The Tom Grahame Trust,
Some tissue samples were obtained from NHS Trusts as part of the UK Brain Archive Information Network (BRAIN-UK) (project 16/007), which is funded by the Medical Research Council.

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