Increased soluble interleukin-2 receptor concentration in plasma predicts a decreased cellular response to IL-2

Abstract

Summary Interleukin 2 (IL-2) immunotherapy has met with limited success in the treatment of renal cell carcinoma (RCC) and malignant melanoma (MM). However, non-responders still account for up to 80% of those patients receiving IL-2. A high concentration of soluble IL-2 receptor (sIL-2R) is commonly found in the blood of such patients. We investigated the possibility that high sIL-2R concentration pretreatment may interfere with the bioavailability of IL-2. The mean concentration of sIL-2R in plasma from patients with MM, RCC and head and neck cancer was 3378 U ml-', 8778 U ml-' and 764 U ml-' respectively, compared with 1315 U ml-' in plasma from healthy volunteers. Inclusion of plasma from patients with RCC and MM patient plasma in cytotoxic T-lymphocyte leukaemic (CTLL) cell/IL-2 assays inhibited the ability of CTLL cells to respond to IL-2, and an inverse correlation was found between the concentration of sIL-2R and the growth response of CTLL cell to IL-2 (r = -0.86, P = 0.003). Plasma with soluble IL-2R concentrations greater than 3000 U ml-' produced a reduction in cell growth of more than 50% when included in CTLL IL-2 assays. The addition of increasing concentrations of IL-2 to cultures containing suppressive plasma failed to restore CTLL cell growth response to normal. Failure to saturate sIL-2R by exogenous IL-2 addition therefore suggests that another factor, initially present at a concentration similar to the sIL-2R concentration, is responsible for the observed effect. Determination of the suppressive effect of patient plasma as presented here may allow more effective IL-2 dosing schedules.

Treatment of metastatic renal cell carcinoma with subcutaneous interleukin 2: evidence for non-renal clearance of cytokines

“…However, CRP is known to form complexes (either calcium-dependent or via polycation binding sites) with many ligands, including nucleic acids and choline phosphatides, subsequently participating in several inflammatory reactions including the activation of complement (Pepys, 1981), which is known to occur during IL-2 therapy. The changes in soluble IL-2 receptors are similar to those reported in other studies (Lindemann et al, 1994;Gooding et al, 1995) and may account for the inhibition of IL-2 in vivo or be involved in its clearance. The detection of some IL-2 bioactivity probably reflects a fraction of IL-2 in equilibrium with its soluble receptor from which it readily dissociates.…”

“…The detection of some IL-2 bioactivity probably reflects a fraction of IL-2 in equilibrium with its soluble receptor from which it readily dissociates. Evidence also suggests that other inhibitors of IL-2 bioactivity may be induced during IL-2 therapy (Gooding et al, 1995), although their identitiy is as yet unknown.…”

Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25

“…Intriguingly, a proportion of MM patients presented high baseline levels of sCD25 (above the median of normal volunteers: 330-1 650 pg/ml [38]). Soluble CD25 reportedly behaves as a decoy receptor or mediates immunosuppressive effects mainly via Tregs [30,31]. Indeed, baseline concentrations of sCD25 in MM patients positively correlated with high circulating Treg numbers in a group of 27 patients whose peripheral blood mononucleated cells (PBMCs) were available [39] (Figure 4F).…”

“…A single infusion of ipilimumab triggered an increase in circulating levels of soluble CD25 (sCD25) and Lag3 in MM patients. High levels of sCD25, which was reported to act as a decoy receptor [30,31], were detrimental for the anticancer activity of anti-mCTLA-4 Ab and ipilimumab in mice and patients, respectively. The best multivariate model calculated based on nine cohorts of 262 MM patients suggests that individuals with sCD25 high LDH high serum signatures at diagnosis are less likely to benefit from ipilimumab therapy than those with low pre-treatment levels of sCD25.…”

Soluble interleukin-2 receptors (sIL-2R) in Hodgkin's disease: outcome and clinical implications

“…Even though its affinity for circulating IL-2 is lower than that for the whole cell-surface receptor, sIL-2R has retained its ability to bind circulating IL-2 (Rubin et al, 1986). Soluble IL-2R can determine a diminished IL-2 biological availability and can consequently be involved in the impaired T-cell function described in Hodgkin's disease patients (Gooding et al, 1995). This compromised host's anti-tumour immunity could lead to unusually aggressive disease.…”