Immunogenomic profiling of circulating T cells in pediatric cancer patients during standard-of-care

Abstract

While pediatric cancer patients receive intensive chemotherapy, its impact on peripheral T cells and subsequently to disease outcomes are not fully characterized. Here, we assessed T-cell dynamics during treatment, identifying associations with outcomes through immune phenotyping and T-cell Receptor (TCR) sequencing in pediatric solid and hematologic malignancies. We show that while levels of immune checkpoint proteins (PD-1, LAG3, and TIM3) at baseline were highest in lymphomas compared to other cancer groups, they increased significantly in response to therapy in all cancers. Levels of Central Memory (CM) T cells increased in leukemias and solid tumors, while naive T cells and cell-free TCR diversity decreased in lymphomas. By combining immune cell and TCR repertoire features across all timepoints, we proposed the Dynamic Immunogenomic Score (DIS) to measure patient-specific effects of therapy on the peripheral T-cell population. Higher DIS was associated with high-risk cancer types and logistic regression analysis revealed it may predict incidence of relapse in leukemia patients. TCR specificity analysis revealed patient-specific clonal dynamics and differential detection of virally-associated TCRs in cancer patients compared to healthy individuals. Our results highlight the potential of early upfront immunogenomic profiling in identifying high-risk patients that may be predictive in light of emerging cellular immunotherapies.