Distinct Immune Signatures Indicative of Treatment Response and Immune-Related Adverse Events in Melanoma Patients under Immune Checkpoint Inhibitor Therapy

To identify potential early biomarkers of treatment response and immune-related adverse events (irAE), a pilot immune monitoring study was performed in stage IV melanoma patients by flow cytometric analysis of peripheral blood mononuclear cells (PBMC). Overall, 17 patients were treated with either nivolumab or pembrolizumab alone, or with a combination of nivolumab and ipilimumab every three weeks. Of 15 patients for which complete response assessment was available, treatment responders (n = 10) as compared to non-responders (n = 5) were characterized by enhanced PD-1 expression on CD8(+) T cells immediately before treatment (median +/- median absolute deviation/MAD 26.7 +/- 10.4% vs. 17.2 +/- 5.3%). Responders showed a higher T cell responsiveness after T cell receptor ex vivo stimulation as determined by measurement of programmed cell death 1 (PD-1) expression on CD3(+) T cells before the second cycle of treatment. The percentage of CD8(+) effector memory (CD8(+)CD45RA(-)CD45RO(+)CCR7(-)) T cells was higher in responders compared to non-responders before and immediately after the first cycle of treatment (median +/- MAD 39.2 +/- 7.3% vs. 30.5 +/- 4.1% and 37.7 +/- 4.6 vs. 24.0 +/- 6.4). Immune-related adverse events (irAE) were accompanied by a higher percentage of activated CD4(+) (CD4(+)CD38(+)HLADR(+)) T cells before the second treatment cycle (median +/- MAD 14.9 +/- 3.9% vs. 5.3 +/- 0.4%). In summary, PBMC immune monitoring of immune-checkpoint inhibition (ICI) treatment in melanoma appears to be a promising approach to identify early markers of treatment response and irAEs.