Erika Negrini

Cancer is the leading cause of death from disease in children. Survival depends not only on surgery, cytostatic drugs, and radiation but also on systemic immune responses. Factors influencing these immune responses in children of different ages and tumor types are unknown. Novel immunotherapies can enhance anti-tumor immune responses, but few children have benefited, and markers of effective responses are lacking. Here, we present a systems-level analysis of immune responses in 191 children within a population-based cohort with diverse tumors and reveal that age and tumor type shape immune responses differently. Systemic inflammation and cytotoxic T cell responses correlate with tumor mutation rates and immune cell infiltration. Clonally expanded T cell responses are rarely detected in blood or tumors at diagnosis but are sometimes elicited during treatment. Expanded T cells are similarly regulated in children and adults with more immunogenic cancers. This research aims to facilitate the development of precision immunotherapies for children with cancer.

Naïve T cell output from the thymus varies across the human lifespan and is a key determinant of health, differing between individuals by age, sex, and genetics. How thymic output is dynamically regulated early in life in response to initial microbial colonization remains unclear. We report longitudinal thymic output dynamics, measured as T cell receptor excision circles (TRECs), in 136 newborns from Stockholm, Sweden. Thymic output increases after birth following initial microbial colonization, peaking at 3-4 mo. Peak height correlates with plasma levels of RANKL and lymphotoxin-α and with a common genetic variant in the TCRD locus previously linked to adult thymopoiesis. B cell lymphopoiesis measured by KRECs reveals divergent dynamics between B and T cell branches of the adaptive immune system in early life. Findings are corroborated by thymic tissue analyses, in which local RANKL secretion correlates with medullary, but not cortical, epithelial cell numbers. These results illuminate the establishment of healthy immune-microbe interactions in early human life.