Highlights
- •The immune contexture of paediatric tumours remains unknown compared with adult cancers.
- •No PD-L1 expression was found on cancer and immune cells of 5 major paediatric cancers.
- •CD163, CSF1R and CD68 myeloid cells were abundant in all tumours except Ewing sarcoma.
- •Some tumours have high levels of infiltrating T-cells but lack efficient activation.
- •Biologically stratified immunotherapy strategies are needed for paediatric oncology.
Abstract
Background
The clinical development of immune checkpoint–targeted immunotherapies has been disappointing
so far in paediatric solid tumours. However, as opposed to adults, very little is
known about the immune contexture of paediatric malignancies.
Methods
We investigated by gene expression and immunohistochemistry (IHC) the immune microenvironment
of five major paediatric cancers: Ewing sarcoma (ES), osteosarcoma (OS), rhabdomyosarcoma
(RMS), medulloblastoma (MB) and neuroblastoma (NB; 20 cases each; n = 100 samples
total), and correlated them with overall survival.
Results
NB and RMS tumours had high immune cell gene expression values and high T-cell counts
but were low for antigen processing cell (APC) genes. OS and ES tumours showed low
levels of T-cells but the highest levels of APC genes. OS had the highest levels of
macrophages (CSF1R, CD163 and CD68), whereas ES had the lowest. MB appeared as immune
deserts. Tregs (FOXP3 staining) were higher in both RMS and OS. Most tumours scored
negative for PD-L1 in tumour and immune cells, with only 11 of 100 samples positive
for PD-L1 staining. PD-L1 and OX40 levels were generally low across all five indications.
Interestingly, NB had comparable levels of CD8 by IHC and by gene expression to adult
tumours. However, by gene expression, these tumours were low for T-cell cytotoxic
molecules GZMB, GZMA and PRF1. Surprisingly, the lower the level of tumour infiltrative
CD8 T-cells, the better the prognosis was in NB, RMS and ES. Gene expression analyses
showed that MYCN-amplified NB have higher amounts of immune suppressive cells such
as macrophages, myeloid-derived suppressor cells and Tregs, whereas the non-MYCN-amplified
tumours were more infiltrated and had higher expression levels of Teff.
Conclusions
Our results describe the quality and quantity of immune cells across five major paediatric
cancers and provide some key features differentiating these tumours from adult tumour
types. These findings explain why anti-PD(L)1 might not have had single agent success
in paediatric cancers. These results provides the rationale for the development of
biologically stratified and personalised immunotherapy strategies in children with
relapsing/refractory cancers.
Keywords
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Article info
Publication history
Published online: May 31, 2022
Accepted:
March 13,
2022
Received:
March 1,
2022
Identification
Copyright
© 2022 Elsevier Ltd. All rights reserved.
