High Soluble Tumor Necrosis Factor Receptor 2 in Serum Is Associated With Inferior Overall Survival Across Major Lymphoma Subtypes

Soluble tumor necrosis factor receptor 2 (sTNFR2) is a member of the TNF superfamily whose normal bodily distribution is largely limited to low level expression on lymphoid cells. It has emerged as an important inducible receptor that activates a signaling pathway for cancer growth. We evaluated sTNFR2 as a prognostic biomarker for overall survival (OS) in newly diagnosed lymphoma using a prospective cohort study with banked pretreatment serum samples. sTNFR2 was higher in 1513 lymphoma patients compared to 499 age and sex matched controls (p < 0.0001). Using Kaplan-Meier curves and Cox proportional hazards models to estimate hazard ratios [HR] (high vs. low tertile), higher levels of sTNFR2 at diagnosis were associated with inferior OS across all seven major lymphoma subtypes: Hodgkin lymphoma (p < 0.0001; HR = 12.6), diffuse large B-cell lymphoma (p < 0.0001; HR = 2.6), follicular lymphoma (p = 0.00017; HR = 2.5), mantle cell lymphoma (p < 0.0001; HR = 4.2), small lymphocytic lymphoma (p = 0.012; HR = 2.4), marginal zone lymphoma (p = 0.0012; HR = 3.1), and T-cell lymphoma (p < 0.0001; HR = 3.1). Using CITE-seq profiling of tumor microenvironment tissue, we sought to identify cellular source(s) of circulating sTNFR2. In tumor tissue from follicular lymphoma, high TNFR2-expressing cells were found to be T-regulatory (Treg) cells, suggestive of a Treg-driven cancer. In tissue from a case of marginal zone lymphoma, high TNFR2 expression was found on CD4+ and CD8+ T cells, B cells, and monocytes but also directly on tumor cells. We conclude sTNRF2 is a strong prognostic biomarker of OS across major lymphoma subtypes and may be useful to guide therapeutic choices, including targeted therapies against immunosuppressive TNFR2-expressing Tregs.