Circulating cytokine dynamics as potential biomarker of response to anti-PD-1 immunotherapy in BRAFwt MM patients

Abstract

Background: The biomarkers of immune checkpoint inhibitors (ICIs) efficacy and safety are still urgently needed. As cytokines are easily detected and monitored in circulation, they could be used as potential predictors of response and immune-related adverse events (irAEs) for ICIs therapy.

Methods: The levels of TGF-β, IFN-γ, IL-6, IL-8, IL-10 were measured in sera and plasma by ELISA method of 30 healthy controls (HC) and 32 BRAF wild type (wt) MM patients before and after every 12 weeks of Pembrolizumab, PD-1 inhibitor, until one year or disease progression (DP).

Results: Higher pretherapy levels of circulating TGF-β, IFN-γ, IL-6, and IL-10 were shown in MM patients compared to HC. In patients with disease control, TGF-β and IL-6 first decreased during the therapy, while then they started to successively increase reaching the initial values by the end of the follow up. Furthermore, in this group of patients IFN-γ increased, while IL-8 and IL-10 decreased at final points of the follow up. In patients with DP IL-6 increased at the time of progression, while IL-8 decreased when the best response was achieved. In patients with pseudoprogression IL-6 and IL-10 significantly increased compared to the pretreatment values. Melanoma patients with irAEs had increased baseline values of TGF-β, IFN-γ, IL-6, and IL-10 compared to HC. However, no significant changes in cytokines levels were found in these patients during therapy.

Conclusions: Inflammatory cytokines monitoring in circulation of BRAFwt MM patients could help in the selection of patients who will have the benefit from Pembrolizumab therapy.

Keywords: BRAF wild type; Cytokines; Metastatic melanoma patients; Monitoring; Outcome predictors; Pembrolizumab.

Graphical abstract

Fig. 1

Pretherapy cytokines levels. Metastatic melanoma patients (MM) have significantly higher levels of TGF-β, IFN-γ, IL-6, and IL-10 compared to healthy controls (HC) (Mann-Whitney test). The results are presented as mean value with standard deviation.

Fig. 2

Cytokines levels in metastatic melanoma (MM) patients without (non-DP) and with disease progression (DP). The dynamics of changes in a) TGF-β, b) IFN-γ, c) IL-6, d) IL-8 and e) IL-10 from baseline (pretherapy) value and after IV, VIII, XII and XVI cycles of anti-PD-1 therapy (Wilcoxon matched-pairs signed rank test) in non-DP MM patients. Results are presented as mean value with range (minimum and maximum); f) In MM patients with DP the level of circulating IL-6 increases at the time of progression, while IL-8 decreases when the best response was achieved compared to the baseline level (Wilcoxon matched-pairs signed rank test). The results are presented as mean value with standard deviation; g) Patients with DP have significantly higher baseline level of IL-6 compared to patients with disease control (complete response (CR), partial response (PR), and stable disease (SD)) (Mann-Whitney test). The results are presented as mean value with standard deviation.

Fig. 3

Cytokines levels during pseudoprogression. The levels of circulating IL-6 and IL-10 significantly increase during pseudoprogression, after 12 weeks of the therapy, compared to the baseline values (Wilcoxon matched-pairs signed rank test). The results are presented as mean value with standard deviation.

Fig. 4

Cytokines levels in metastatic melanoma (MM) patients with immune-related adverse events. MM patients with immune-related adverse events have significantly higher baseline levels of TGF-β, IFN-γ, IL-6, and IL-10 compared to HC (Mann–Whitney exact test). The results are presented as mean value with standard deviation.