Soluble CD163 predicts outcome in both chemoimmunotherapy and targeted therapy–treated mantle cell lymphoma

Abstract

The outcome for patients with mantle cell lymphoma (MCL) has drastically improved with new treatments directed towards the tumor immune microenvironment, where macrophages play an important role. In MCL, the presence of M2 macrophages defined by CD163 expression in diagnostic biopsies has been associated with a worse prognosis. An alternative way to assess the abundance of M2 macrophages is by measuring the level of soluble CD163 in serum (sCD163). We aimed to investigate the prognostic value of sCD163 in 131 MCL patients. We found that high sCD163 at diagnosis was associated with shorter progression-free survival (PFS) and shorter overall survival (OS) (p=0.002 and p<0.001) in 81 newly diagnosed chemoimmunotherapy-treated patients. The same was seen in a cohort of 50 relapsed MCL patients mainly treated within the phase II Philemon-trial with rituximab, ibrutinib and lenalidomide (PFS p=0.016 and OS p=0.035). In newly diagnosed patients with low levels of sCD163, five-year survival was 97%. There was a moderate correlation between sCD163 and tissue CD163 (r=0.64, p=0.014). The association with a poor prognosis was independent of MIPI, Ki67, p53 status and blastoid morphology, as assessed in a multivariable Cox proportional hazards model. Here, high sCD163 was associated with both shorter PFS (HR 3.48 95% CI: 1.42-8.54) and shorter OS (HR 4.33 95% CI: 1.32-14.2), showing that high levels of the M2 macrophage marker sCD163 is an independent negative prognostic factor in MCL, both in the chemoimmunotherapy and ibrutinib/lenalidomide era. In addition, low sCD163 levels identify MCL patients with a very good prognosis.

Serum-Soluble CD163 Levels as a Prognostic Biomarker in Patients with Diffuse Large B-Cell Lymphoma Treated with Chemoimmunotherapy

“…In a recent publication by Xiaoqing Sun, Siglec-5/CD163 values constituted an independent biomarker in DLBCL [ 46 ]. In addition, Nikkarinen et al reported the impact of serum sCD163, detected by an ELISA, in patients with mantle cell lymphoma treated with immunotherapy [ 47 ].…”

Empowering macrophages: the cancer fighters within the tumour microenvironment in mantle cell lymphoma

“…This is not surprising, since it is known from the literature that macrophages correlate with poorer prognosis in many lymphoma subtypes ( 46 , 57 – 60 ). However, this knowledge has only recently begun being utilized in predicting prognosis ( 19 ), identifying soluble markers ( 18 ) and enhancing the efficacy of novel immunotherapy treatments in the MCL setting ( 61 ).…”

“…We have previously confirmed the prognostic value of CD163 by measuring soluble CD163 (sCD163) in the serum of patients with MCL. High sCD163 was associated with shorter progression-free survival and poor outcome in patients treated with rituximab, ibrutinib and lenalidomide in a phase 2 clinical trial ( 18 ). Although sCD163 levels were higher in patients with p53-deficient tumours, the prognostic value of sCD163 was independent of TP53 mutations and other clinical factors such as MIPI, Ki-67 or blastoid morphology, while low sCD163 levels could identify patients with a favourable prognosis ( 18 ).…”

“…High sCD163 was associated with shorter progression-free survival and poor outcome in patients treated with rituximab, ibrutinib and lenalidomide in a phase 2 clinical trial ( 18 ). Although sCD163 levels were higher in patients with p53-deficient tumours, the prognostic value of sCD163 was independent of TP53 mutations and other clinical factors such as MIPI, Ki-67 or blastoid morphology, while low sCD163 levels could identify patients with a favourable prognosis ( 18 ). Various clinical approaches have been investigated to target M2-like macrophages and disrupt MCL proliferative advantage.…”

“…Markers for poor prognosis that are used in the clinic include a high mantle cell lymphoma international prognostic index (MIPI), high proliferation rate measured with Ki-67, blastoid and/or pleomorphic histology, as well as an abnormal karyotype ( 13 – 17 ). However, it has become clear that patient outcome cannot be determined by studying only the disease-specific cell types, but must include the much wider system of supporting and interacting cells that constitute the TME ( 18 – 20 ). The tumour architecture, presence and composition of inflammatory cells in the tumour tissue, and soluble biomarkers are important aspects of the TME.…”