Defining the Inflammatory Plasma Proteome in Pediatric Hodgkin Lymphoma

SIMPLE SUMMARY: Hodgkin lymphoma (HL) is a common type of cancer that is characterized by rare, malignant cells among an inflammatory microenvironment. Specific systemic, inflammatory plasma proteins have demonstrated prognostic significance in adult HL; however, systemic inflammation has not been well-characterized in childhood HL. The aim of our study was to better define the inflammatory pre-therapy plasma proteome and identify plasma proteins associated with clinical features of childhood HL. We measured plasma concentrations of 135 proteins in 56 pediatric subjects with newly diagnosed HL and 47 healthy pediatric controls. We found that the plasma protein profile was distinct from controls, and unique proteins were associated with high-risk disease (IL-10, TNF-α, IFN-γ, IL-8), slow early therapy response (CCL13, IFN-λ1, IL-8), and relapse (TNFSF10). These proteins could be used to improve risk stratification, and thus optimize outcomes and minimize unnecessary toxic exposures for those with childhood HL. ABSTRACT: Hodgkin lymphoma (HL) histopathology is characterized by rare malignant Reed–Sternberg cells among an inflammatory infiltrate. We hypothesized that characteristics of inflammation in pediatric HL lesions would be reflected by the levels of inflammatory cytokines or chemokines in pre-therapy plasma of children with HL. The study objectives were to better define the inflammatory pre-therapy plasma proteome and identify plasma biomarkers associated with extent of disease and clinical outcomes in pediatric HL. Pre-therapy plasma samples were obtained from pediatric subjects with newly diagnosed HL and healthy pediatric controls. Plasma concentrations of 135 cytokines/chemokines were measured with the Luminex platform. Associations between protein concentration and disease characteristics were determined using multivariate permutation tests with false discovery control. Fifty-six subjects with HL (mean age: 13 years, range 3–18) and 47 controls were analyzed. The cytokine/chemokine profiles of subjects with HL were distinct from controls, and unique cytokines/chemokines were associated with high-risk disease (IL-10, TNF-α, IFN-γ, IL-8) and slow early response (CCL13, IFN-λ1, IL-8). TNFSF10 was significantly elevated among those who ultimately relapsed and was significantly associated with worse event-free survival. These biomarkers could be incorporated into biologically based risk stratification to optimize outcomes and minimize toxicities in pediatric HL.