Revisiting IL-6 expression in the tumor microenvironment of classical Hodgkin lymphoma
Alex Reza Gholiha, Peter Hollander, Ingrid Glimelius, Gustaf Hedström, Daniel Molin, Henrik Hjalgrim, Karin E. Smedby, Jamileh Hashemi, Rose‐Marie Amini, Gunilla Enblad
Abstract
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-6+ leukocytes and IL-6+ 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 = 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-6+ leukocytes ≥1% (n = 54 of 136) had inferior event-free survival (hazard ratio [HR] = 3.58; 95% confidence interval [CI], 1.80-7.15) and overall survival (HR = 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-6+ HRS cells and high serum IL-6 levels were not associated with survival. IL-6+ leukocytes correlated with increased proportions of IL-6+ HRS cells (P < .01), CD138+ plasma cells (P < .01), CD68+ macrophages (P = .02), and tryptase-positive mast cells (P < .01). IL-6+ HRS cells correlated with increased proportions of CD68+ macrophages (P = .03), programmed death-ligand 1-positive (PD-L1+) leukocytes (P = .04), and PD-L1+ 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-6+ leukocytes in the TME in a cohort of contemporarily treated adult patients with cHL.