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.

Immune-related signature identifies IL1R2 as an immunological and prognostic biomarker in pancreatic cancer

“…First, it was found that the mutation frequency of all 4 driver genes of PC (KRAS, TP53, CDKN2A, SMAD4) were significantly elevated in the IL1R2 high expression group. Additionally, TMB, a biomarker closely associated with improved immunotherapies, [ 48 ] was proved to be increased in the IL1R2 high expression group. Combined with the IPS algorithm, it was found that patients in IL1R2 high expression possessed a relatively higher probability of responding to anti-PD1 therapy, anti-CTLA4 therapy and the combination of anti-PD1 and anti-CTLA-4 therapy.…”

Immune Microenvironment in Childhood Cancers: Characteristics and Therapeutic Challenges

“…Molecular profiling of the immune microenvironment of high-risk pediatric tumors based on Immune Pediatric Signature Score (IPASS), which combines immunohistochemistry staining data of T lymphocytes with RNA and whole-genome sequencing, estimated that 31% of high-risk cancers in pediatric patients have infiltrating T cells [ 23 ]. In CNS tumors, pediatric gliomas have the most T-cell receptor (TCR) clones, while osteosarcoma and neuroblastoma show more diversity in these clones.…”

“…This diversity in TCR repertoires is linked to prognosis and response to immune therapy in these tumors. Interestingly, the study found that tumor mutational burden (TMB) and neoantigen load, which reflect genetic changes in cancer cells, did not predict T-cell infiltration in pediatric cancers [ 23 ]. This implies that the presence of a high TMB or a large number of neoantigens may not necessarily correlate with increased T-cell infiltration and immune response in these cancers.…”

Management of locally advanced non‐small cell lung cancer: State of the art and future directions

“…[ 72 ] scanned the entire immune microenvironment and found a decreased number of intratumoral‐activated Tregs in MPR tumors, along with clonal expansion of peripheral cytotoxic CD8 + T cells. Another study revealed therapy‐promoting expansion of cytotoxic T cells and activation of memory CD8 + T cells into an effector phenotype, as well as MPR‐associated reduction of neutrophil heterogeneity in the aged CCL3 + neutrophil/secreted phosphoprotein 1(+)/tumor‐associated macrophage pathway [ 73 ].…”