@article{40352981af674a44b61abf7d4dcbdeef,
title = "A novel transcriptional signature identifies T-cell infiltration in high-risk paediatric cancer",
abstract = "Background: Molecular profiling of the tumour immune microenvironment (TIME) has enabled the rational choice of immunotherapies in some adult cancers. In contrast, the TIME of paediatric cancers is relatively unexplored. We speculated that a more refined appreciation of the TIME in childhood cancers, rather than a reliance on commonly used biomarkers such as tumour mutation burden (TMB), neoantigen load and PD-L1 expression, is an essential prerequisite for improved immunotherapies in childhood solid cancers. Methods: We combined immunohistochemistry (IHC) with RNA sequencing and whole-genome sequencing across a diverse spectrum of high-risk paediatric cancers to develop an alternative, expression-based signature associated with CD8+ T-cell infiltration of the TIME. Furthermore, we explored transcriptional features of immune archetypes and T-cell receptor sequencing diversity, assessed the relationship between CD8+ and CD4+ abundance by IHC and deconvolution predictions and assessed the common adult biomarkers such as neoantigen load and TMB. Results: A novel 15-gene immune signature, Immune Paediatric Signature Score (IPASS), was identified. Using this signature, we estimate up to 31% of high-risk cancers harbour infiltrating T-cells. In addition, we showed that PD-L1 protein expression is poorly correlated with PD-L1 RNA expression and TMB and neoantigen load are not predictive of T-cell infiltration in paediatrics. Furthermore, deconvolution algorithms are only weakly correlated with IHC measurements of T-cells. Conclusions: Our data provides new insights into the variable immune-suppressive mechanisms dampening responses in paediatric solid cancers. Effective immune-based interventions in high-risk paediatric cancer will require individualised analysis of the TIME.",
keywords = "Biomarkers, Paediatric cancer, T-cell infiltration, Transcriptome signature, Tumour immune microenvironment",
author = "Chelsea Mayoh and Gifford, {Andrew J.} and Rachael Terry and Lau, {Loretta M.S.} and Marie Wong and Padmashree Rao and Tyler Shai-Hee and Federica Saletta and Khuong-Quang, {Dong Anh} and Vicky Qin and Mateos, {Marion K.} and Deborah Meyran and Miller, {Katherine E.} and Aysen Yuksel and Mould, {Emily V.A.} and Rachel Bowen-James and Dinisha Govender and Akanksha Senapati and Nataliya Zhukova and Natacha Omer and Hetal Dholaria and Frank Alvaro and Heather Tapp and Yonatan Diamond and Pozza, {Luciano Dalla} and Moore, {Andrew S.} and Wayne Nicholls and Gottardo, {Nicholas G.} and Geoffrey McCowage and Hansford, {Jordan R.} and Khaw, {Seong Lin} and Wood, {Paul J.} and Daniel Catchpoole and Cottrell, {Catherine E.} and Mardis, {Elaine R.} and Marshall, {Glenn M.} and Vanessa Tyrrell and Michelle Haber and Ziegler, {David S.} and Orazio Vittorio and Trapani, {Joseph A.} and Cowley, {Mark J.} and Neeson, {Paul J.} and Ekert, {Paul G.}",
note = "Funding Information: This work has been funded by the Australian Federal Government Department of Health, the New South Wales State Government and the Australian Cancer Research Foundation for funding to establish infrastructure to support the Zero Childhood Cancer personalised medicine programme. Funding from the Kids Cancer Alliance, Cancer Therapeutics Cooperative Research Centre supports the development of a personalised medicine programme; Tour de Cure supports tumour biobank personnel; the Steven Walter Children{\textquoteright}s Cancer Foundation and the Hyundai Help 4 Kids Foundation support G.M.M. and P.G.E.; Samuel Nissen Charitable Foundation supports P.G.E.; the Lions Kids Cancer Genome Project is a joint initiative of Lions International Foundation, the Australian Lions Children{\textquoteright}s Cancer Research Foundation (ALCCRF), the Garvan Institute of Medical Research, the Children{\textquoteright}s Cancer Institute and the Kids Cancer Centre, Sydney Children{\textquoteright}s Hospital. Lions International and ALCCRF provided funding to perform WGS and for key personnel, with thanks to J. Collins for project governance and advocacy. The Cure Brain Cancer Foundation supports the RNA sequencing of patients with brain tumours; the Kids Cancer Project supports molecular profiling and molecular and clinical trial personnel; and the University of New South Wales, W. Peters and the Australian Genomics Health Alliance provide personnel funding support. The Medical Research Future Fund, Australian Brain Cancer Mission/National Health & Medical Research Council/Lifting Clinical Trials and Registry Capacity (NHMRC MRF9500002), the Minderoo Foundation{\textquoteright}s Collaborate Against Cancer Initiative and funds raised through the Zero Childhood Cancer Capacity Campaign, a joint initiative of Children{\textquoteright}s Cancer Institute and the Sydney Children{\textquoteright}s Hospital Foundation, supported the national clinical trial and associated clinical and research personnel. Cancer Institute of New South Wales and New South Wales Health (fellowship funding for M.J.C.; CINSW Early Career Fellowship 181430 for M.K.M; CINSW Program Grant 2019/TPG2037). National Health and Medical Research Council (career development fellowship APP1164960 for O.V.). This research was supported by an Australian Government Research Training Program (RTP) Scholarship (for C.M.). This research was supported by Tour de Cure and the Australia and New Zealand Sarcoma Association (funding for R.T.). The 2018 Priority-Driven Collaborative Cancer Research Scheme, co-funded by Cancer Australia and My Room, for personnel and computational support (grant no. 1165556 awarded to M.J.C.). Funding Information: We sincerely thank patients and parents for participating in this study. We thank the many clinicians, tumour banks and health professionals for their time acquiring consent for patients and for the collection and coordination of samples and associated clinical data at Sydney Children{\textquoteright}s Hospital, Randwick; the Children{\textquoteright}s Hospital at Westmead; the John Hunter Children{\textquoteright}s Hospital; the Queensland Children{\textquoteright}s Hospital; the Royal Children{\textquoteright}s Hospital Melbourne; the Monash Children{\textquoteright}s Hospital; the Adelaide Women & Children{\textquoteright}s Hospital; and the Perth Children{\textquoteright}s Hospital. Tumour samples and coded data were supplied by the Children{\textquoteright}s Cancer Centre Biobank at the Murdoch Children{\textquoteright}s Research Institute and The Royal Children{\textquoteright}s Hospital (mcri.edu.au/research/projects/childrens-cancer-centre-biobank). The establishment and running of the Children{\textquoteright}s Cancer Centre are made possible through generous support by Cancer In Kids @ RCH ( www.cika.org.au ), the Royal Children{\textquoteright}s Hospital Foundation and the Murdoch Children{\textquoteright}s Research Institute. We thank ANZCHOG as the trial sponsor, and we thank the staff of the Personalised Medicine Theme of the Children{\textquoteright}s Cancer Institute for their dedicated work on the Zero Childhood Cancer Program. We thank the Biomedical Imaging Facility (BMIF) at UNSW for the access to instruments through which the imaging component of the IHC analysis for this study was carried out. Zero Childhood Cancer is a joint initiative led by the Children{\textquoteright}s Cancer Institute and the Kids Cancer Centre, Sydney Children{\textquoteright}s Hospital, Randwick. K.E.M., C.E.C. and E.R.M. wish to thank the Nationwide Foundation Pediatric Innovation Fund (Columbus, OH, USA). The authors would like to acknowledge Luminesce Alliance—Innovation for Children{\textquoteright}s Health for its contribution and support. Luminesce Alliance—Innovation for Children{\textquoteright}s Health is a not-for-profit cooperative joint venture between the Sydney Children{\textquoteright}s Hospitals Network, the Children{\textquoteright}s Medical Research Institute and the Children{\textquoteright}s Cancer Institute. It has been established with the support of the NSW Government to coordinate and integrate paediatric research. Luminesce Alliance is also affiliated with the University of Sydney and the University of New South Wales Sydney. Funding Information: We sincerely thank patients and parents for participating in this study. We thank the many clinicians, tumour banks and health professionals for their time acquiring consent for patients and for the collection and coordination of samples and associated clinical data at Sydney Children{\textquoteright}s Hospital, Randwick; the Children{\textquoteright}s Hospital at Westmead; the John Hunter Children{\textquoteright}s Hospital; the Queensland Children{\textquoteright}s Hospital; the Royal Children{\textquoteright}s Hospital Melbourne; the Monash Children{\textquoteright}s Hospital; the Adelaide Women & Children{\textquoteright}s Hospital; and the Perth Children{\textquoteright}s Hospital. Tumour samples and coded data were supplied by the Children{\textquoteright}s Cancer Centre Biobank at the Murdoch Children{\textquoteright}s Research Institute and The Royal Children{\textquoteright}s Hospital (mcri.edu.au/research/projects/childrens-cancer-centre-biobank). The establishment and running of the Children{\textquoteright}s Cancer Centre are made possible through generous support by Cancer In Kids @ RCH (www.cika.org.au), the Royal Children{\textquoteright}s Hospital Foundation and the Murdoch Children{\textquoteright}s Research Institute. We thank ANZCHOG as the trial sponsor, and we thank the staff of the Personalised Medicine Theme of the Children{\textquoteright}s Cancer Institute for their dedicated work on the Zero Childhood Cancer Program. We thank the Biomedical Imaging Facility (BMIF) at UNSW for the access to instruments through which the imaging component of the IHC analysis for this study was carried out. Zero Childhood Cancer is a joint initiative led by the Children{\textquoteright}s Cancer Institute and the Kids Cancer Centre, Sydney Children{\textquoteright}s Hospital, Randwick. K.E.M., C.E.C. and E.R.M. wish to thank the Nationwide Foundation Pediatric Innovation Fund (Columbus, OH, USA). The authors would like to acknowledge Luminesce Alliance—Innovation for Children{\textquoteright}s Health for its contribution and support. Luminesce Alliance—Innovation for Children{\textquoteright}s Health is a not-for-profit cooperative joint venture between the Sydney Children{\textquoteright}s Hospitals Network, the Children{\textquoteright}s Medical Research Institute and the Children{\textquoteright}s Cancer Institute. It has been established with the support of the NSW Government to coordinate and integrate paediatric research. Luminesce Alliance is also affiliated with the University of Sydney and the University of New South Wales Sydney. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = dec,
doi = "10.1186/s13073-023-01170-x",
language = "English",
volume = "15",
journal = "Genome Medicine",
issn = "1756-994X",
publisher = "BioMed Central",
number = "1",
}
