Discussion
tumor, cancers, T-cell clonotypes, TCRβ, PD
INFILTRATING, TUMOR, PEDIATRIC CANCER, CANCERS
We report on the exploratory immunogenomic biomarker analysis of tumor samples from children with refractory/relapsed cancers before treatment with the anti-PD-L1 antibody, atezolizumab, in the iMATRIX-atezo studyOne hurdle in the interpretation of PD-L1 as a robust biomarker is the spectrum of antibodies and scoring methodologies used, resulting in a lack of consensus in interpretation and applicability of PD-L1 to pediatric cancersIn iMATRIX-atezo, TMB > 2.6 mut per Mb (dataset median) measured by the F1 assay was not associated with higher levels of T cells or improved PFS. As pediatric cancers have generally lower overall mutation burden than adultsWe explored infiltrating TCRβ diversity as a predictor of survival in pediatric patients treated with atezolizumab and observed a trend toward improved PFS with higher TCRβ diversity, but not with TCRβ specificity groups. Considering a report showing how different T-cell clonotypes targeting the same mutations evolve over timeDGE analysis between patients with PR/SD versus PD provided biological insights into atezolizumab activity. The top highly upregulated gene, Higher expression of The gene co-expression network analysis identified core pathways in the pediatric tumor microenvironment associated with improved PFS. PedCAP scores were associated with PFS in pediatric and adult cancers treated with ICI and consisted of genes critical for T-cell functions expressed in several cell types. These include genes encoding CD3 chains, CD2 co-stimulatory molecule and Our work identified a series of potential biomarkers that can predict response to atezolizumab across pediatric cancers. Although they require validation in a larger dataset, our findings highlight the value of clinical genomics and RNA-seq to nominate patients for ICI therapy