Soluble immune checkpoints HVEM and TIM‐3 are prognostic biomarkers for outcome in classical Hodgkin lymphoma

Abstract

Introduction: Immune checkpoints expressed in the tumor microenvironment (TME) play a key role in the immune evasion of cancer in general and in classical Hodgkin lymphoma (cHL) in particular. While few studies reported elevated PD-L1 serum levels in cHL compared to healthy individuals, the distribution and prognostic significance of soluble immune checkpoints (sCP) in the serum of cHL patients remains unclear. We therefore analyze the prognostic value of 14 different baseline sCP levels in prospectively treated patients with primary cHL. Methods: We measured serum levels of soluble BTLA, CD27, CD80, CTLA-4, GITR, GITR-L, HVEM, MICA, MICB, PD-L1, TIM-3, ULBP-1, ULBP-3, ULBP-4 with multiplex cytokine arrays in patients treated in the German Hodgkin Study Group (GHSG) trials HD7, HD8 and HD9. We designed a PFS-event-enriched study cohort from these patients. sCP levels were analyzed descriptively. In absence of validated thresholds, associations of sCP serum levels with PFS and OS were first tested using weighted cox-regression stratified for stage, age and sex, modeling sCP levels as continuous variables before performing secondary analyses separating levels into three groups: low, medium and high. All analyses of PFS and OS were weighted with respect to the proportion of progressions and relapses in the total study population to correct for event-enrichment. Results: Of 308 patients with measured sCP levels, 176 (57.1%) had advanced stage disease and median follow-up was 144 months. Weak correlations were noted among sCPs (median r = 0.12, IQR 0.24). Only TIM-3 and HVEM were significantly associated with PFS and OS by cox-regression modeling sCP levels as continuous variables. Interestingly, no associations of soluble PD-L1 with outcome was observed (PFS: p = 0.22, OS: p = 0.54). PFS and OS differed significantly when the cohort was split by TIM-3 sCP levels (p = 0.014 and 0.003, respectively for PFS and OS) but not when split by HVEM sCP levels (p = 0.051 and 0.2). In detail, Patients with TIM-3 serum levels in the upper third of levels had a higher risk of progression (HR 2.3, CI95: 1.3–4.0) or death (HR: 2.5 CI95: 1.2–5.4) compared to those in the lower third. High HVEM was associated with significantly shorter PFS (HR 1.8, CI95: 1.1–3.2) but not shorter OS (HR 1.6, CI95: 0.6–3.2). Exploratory separation by median rendered similar results. Keywords: Diagnostic and Prognostic Biomarkers, Hodgkin lymphoma No conflicts of interests pertinent to the abstract.