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Lack of acid sphingomyelinase (ASM) activity, either through genetic deficiency or through pharmacological inhibition, is linked with increased activity and frequency of Foxp3+ regulatory T cells (Treg) among cluster of differentiation (CD) 4+ T cells in mice in vivo and in vitro1. Thus, pharmacological blockade of ASM activity, which catalyzes the cleavage of sphingomyelin to ceramide and phosphocholine, might be used as a new therapeutic mechanism to correct numeric and/ or functional Treg de-ficiencies in diseases like multiple sclerosis or major depression.
In the present study, the effect of pharmacological inhibition of ASM in humans, in vitro and in vivo, was analyzed. In the in vitro experiments, peripheral blood mono-nuclear cells (PBMC) of healthy human blood donors were treated with two widely prescribed antidepressants with high (sertraline, Ser) or low (citalopram, Cit) capaci-ty to inhibit ASM activity. Similar to the findings in mice an increase in the frequency of Treg among human CD4+ T cells upon inhibition of ASM activity was observed. For the analysis in vivo, a prospective study of the composition of the CD4+ T cell com-partment of patients treated for major depression was done. The data show that pharmacological inhibition of ASM activity was superior to antidepressants with little or no ASM-inhibitory activity in increasing CD45RA- CD25high effector Treg (efTreg) frequencies among CD4+ T cells to normal levels. Independently of ASM inhibition, correlating the data with the clinical response, i.e. improvement of the Hamilton rat-ing scale for depression (HAMD) by at least 50 per cent (%) after four weeks of treatment, it was found that an increase in efTreg frequencies among CD4+ cells dur-ing the first week of treatment identified patients with a clinical response.
Regarding the underlying mechanism, it could be found that the positive effect of ASM inhibition on Treg required CD28 co-stimulation suggesting that enhanced CD28 co-stimulation was the driver of the observed increase in the frequency of Treg among human CD4+ T cells. Inhibition of ASM activity was further associated with changes in the expression and shuttling of CTLA-4, a key inhibitory molecule ex-pressed by Treg, between cellular compartments but the suppressive activity of CTLA-4 through its transendocytosis activity was unaffected by the inhibition of ASM activity.
In summary, the frequency of (effector) Treg among CD4+ T cells in mice and in hu-mans is increased after inhibition of ASM activity suggesting that ASM blockade might beneficially modulate autoimmune diseases and depression-promoting in-flammation.
Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A, n = 52) versus those who received only one treatment line of ICB (cohort B, n = 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups (p = 0.1) with a median OS of 16.2 months (cohort A, 95% CI: 11.1–23.8) versus 9.4 months (cohort B, 95% CI: 6.1–14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities.