Background: Cancer is the leading cause of death from disease in children. Curing cancer requires cytostatic drugs and radiation, as well as systemic immune responses to clear malignant cells. Determinants of such responses in children of different ages and with different tumors are unknown. Novel immunotherapies can potentiate anti-tumor immune responses, but so far, very few children with solid tumors have benefitted and markers of productive anti-tumor immune responses in children are lacking.

Methods: 119 children at the Section for Pediatric Oncology, Astrid Lindgren Children’s Hospital, Karolinska University Hospital in Stockholm, Sweden, diagnosed with solid tumors were recruited to Immune Systems Against Cancer in Children (ISAC) cohort from March 2018 to April 2021. Whole blood samples were collected for immune cell composition (Mass cytometry), plasma protein abundances (Olink assays), transcriptomics, and clonality analysis. Whole genome sequencing data from tumor tissue of children included in the ISAC cohort was obtained from the Swedish Childhood Tumor Biobank and was used for mutational load and signatures analysis.

Results: We find that the variation among systemic immune system states is determined predominantly by tumor type, and not age or sex as is the case among healthy children. We also show that specific groups of tumors elicit similar immune response states, which could inspire future updates to treatment protocols for such cancers. This illustrates the potential of this unbiased approach and inclusion of children with diverse solid tumors, whereby shared patterns can lead to novel hypotheses regarding underlying mechanisms among groups of patients, rarely considered together in more reductionist studies of individual tumor types. We also report that general, as well as specific, mutational profiles of neuroblastomas are associated with specific differences in immune responses and finally, we show that clonally expanded T cell responses are rarely observed at baseline in children but can be elicited by successful treatments and monitored as biosensors of therapeutic responses enabling precision oncology in the future. Such monitoring should be considered a complement to the already established precision medicine approaches based on tumor genetics.

Conclusions: Our findings suggest the importance of systemic immunity in coordinating and sustaining immune responses against tumors, but also that the developmental changes in human immune systems must be considered when developing and applying new immunotherapeutic interventions for children of different ages with various tumors. Our findings could also inspire the development of future strategies to trigger more productive immune responses against tumors in children.

Citation Format: Qi Chen, Binbin Zhao, Ziyang Tan, Gustav Hedberg, Jun Wang, Laura Gonzalez, Constantin Mugabo, Anette Johnsson, Laura Páez, Lucie Rodriguez, Anna James, Yang Chen, Jaromir Mikes, Hugo Barcenilla, Chunlin Wang, Mark M. Davis, Lena-Maria Carlson, Niklas Pal, Nikolas Herold, Klas Blomgren, Dirk Repsilber, Tadepally Lakshmikanth, Per Kogner, Linda Ljungblad, Petter Brodin. Systems-level immunomonitoring in children with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6378.