Transcriptional immunogenomic analysis reveals distinct immunological clusters in pediatric nervous system tumours

Arash Nabbi; Pengbo Beck; Alberto Delaidelli; Derek A. Oldridge; Sumedha Sudhaman; Kelsey Zhu; Shuo Yang; David T. Mulder; Jeffrey P. Bruce; Joseph Nathaniel Paulson; Pichai Raman; Yuankun Zhu; Adam Cain Resnick; Poul H. B. Sorensen; Martin Sill; Sebastian Brabetz; Sander Lambo; David M. Malkin; Pascal David Johann; Marcel Kool; David Jones; Stefan Michael Pfister; Natalie Jäger; Trevor J. Pugh

doi:10.1101/2022.09.20.508719

GenomicsbioRxivSep 20, 2022

Preprint

Transcriptional immunogenomic analysis reveals distinct immunological clusters in pediatric nervous system tumours

Arash Nabbi iD, Pengbo Beck iD, Alberto Delaidelli iD, Derek A. Oldridge iD, Sumedha Sudhaman iD, Kelsey Zhu iD, Shuo Yang iD, David T. Mulder iD, Jeffrey P. Bruce iD, Joseph Nathaniel Paulson iD, Pichai Raman iD, Yuankun Zhu iD, Adam Cain Resnick iD, Poul H. B. Sorensen iD, Martin Sill iD, Sebastian Brabetz iD, Sander Lambo iD, David M. Malkin iD, Pascal David Johann iD, Marcel Kool iD, David Jones iD, Stefan Michael Pfister iD, Natalie Jäger iD, Trevor J. Pugh iD

Abstract

To inform immunotherapy approaches in children, we performed an immunogenomic analysis of RNA-seq data from 925 treatment-naive pediatric nervous system tumours (pedNST) spanning 12 cancer types from three public data sets. Within pedNST, we uncovered four broad immune clusters: Pediatric Inflamed (10%), Myeloid Predominant (30%), Immune Neutral (43%) and Immune Excluded (17%). We validated these clusters using immunohistochemistry, methylation immune inference, and segmentation analysis of tissue images. We report shared biology of these immune clusters within and across cancer types, and characterization of specific immune-cell frequencies as well as T- and B-cell repertoires. We found no associations between immune infiltration levels and tumour mutational burden, although molecular cancer entities were enriched within specific immune clusters. Given the heterogeneity within pedNST, our findings suggest personalized immunogenomic profiling is needed to guide selection of immunotherapeutic strategies.

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