Revisiting IL-6 expression in the tumor microenvironment of classical Hodgkin lymphoma

Interleukin-6 (IL-6) can induce therapeutic resistance for several cancer agents currently used to treat classical Hodgkin lymphoma (cHL). We aimed to investigate whether the presence of IL-61 leukocytes and IL-61 Hodgkin-Reed-Sternberg (HRS) cells in the tumor microenvironment (TME) was associated with adverse survival outcomes, expression of other immune markers, and serum IL-6 levels. We used a contemporarily treated cohort (n 5 136), with a median follow-up of 13.8 years (range, 0.59-15.9 years). We performed immunohistochemistry with an IL-6 antibody on tissue microarrays from diagnostic biopsies of cHL patients. Patients with IL-61 leukocytes $1% (n 5 54 of 136) had inferior event-free survival (hazard ratio [HR] 5 3.58; 95% confidence interval [CI], 1.80-7.15) and overall survival (HR 5 6.71; 95% CI, 2.51-17.99). The adverse survival was maintained in multivariate Cox regression and propensity score-matched analyses, adjusting for well-known poor-prognostic covariates. The presence of IL-61 HRS cells and high serum IL-6 levels were not associated with survival. IL-61 leukocytes correlated with increased proportions of IL-61 HRS cells (P,.01), CD1381 plasma cells (P,.01), CD681 macrophages (P 5.02), and tryptase-positive mast cells (P,.01). IL-61 HRS cells correlated with increased proportions of CD681 macrophages (P 5.03), programmed death-ligand 1-positive (PD-L11) leukocytes (P 5.04), and PD-L11 HRS cells (P,.01). Serum-IL-6 lacked correlation with IL-6 expression in the TME. This is the first study highlighting the adverse prognostic impact of IL-61 leukocytes in the TME in a cohort of contemporarily treated adult patients with cHL.