Immunoprofiling, sex- and age-related determinants of treatment response in paediatric, adolescent and young adult Hodgkin lymphoma.

The study investigates how sex and age influence treatment response in paediatric, adolescent and young adult (AYA) classical Hodgkin lymphoma (cHL), integrating clinical data, immune-gene profiling and metabolic imaging from the European Network for Paediatric Hodgkin Lymphoma (EuroNet-PHL-C2 trial). cHL patients treated in Italian Association of Pediatric Hematology & Oncology Research (AIEOP) centres (2018-2020) underwent fluorodeoxyglucose-positron emission tomography (FDG-PET) at baseline, after two chemotherapy cycles early response assessment (ERA) and post-chemotherapy (late response assessment, LRA). Responses were classified as early complete metabolic response (CMR) or as adequate response (AR), inadequate (IR) or progressive disease at LRA. Tumour samples were profiled for 730 immune-related genes, and clinical and quantitative positron emission tomography parameters were integrated to assess sex- and age-related patterns. Sixty-eight cases passed quality control. Early CMR occurred in 51.5% at ERA; 29.4% showed (AR) at LRA. Older age (≥13 years), especially in males, was associated with higher IR risk. runt-related transcription factor 3 (RUNX3) expression characterized CMR; a five-gene panel (Bone Marrow Stromal Cell Antigen-1/CD157 [BST1]; C-X-C Motif Chemokine Receptor 6 [CXCR6]; Inducible T-cell Co-stimulator/CD278 [ICOS], Ubiquitin Specific Peptidase 9 Y-Linked [USP9Y], and Single Ig IL-1-Related Receptor/IL-1R8 [SIGIRR]) predicted IR and reflected sex-related immune differences. USP9Y expression correlated with baseline tumour volume (total metabolic tumour volume, TMTV1). Combining TMTV1 with RUNX3 improved CMR discrimination, while TMTV1 with the five-gene panel increased sensitivity but reduced accuracy at LRA. Sex and age influence immune response in AYA cHL. RUNX3 and the five-gene panel show promise as biomarkers of early and late response.