Low baseline levels of NK cells may predict a positive response to ipilimumab in melanoma therapy

The introduction of immune checkpoint blockade (ICB) has been a breakthrough in the therapy of metastatic melanoma. The influence of ICB on T-cell populations has been studied extensively, but little is known about the effect on NK cells. In this study, we analysed the relative and absolute amounts of NK cells and of the subpopulations of CD56(dim) and CD56(bright) NK cells among the peripheral blood mononuclear cells (PBMCs) of 32 patients with metastatic melanoma before and under treatment with ipilimumab or pembrolizumab by flow cytometry. In 15 (47%) patients, an abnormal low amount of NK cells was found at baseline. Analysis of the subpopulations showed also low or normal baseline levels for CD56(dim) NK cells, whereas the baseline levels of CD56(bright) NK cells were either normal or abnormally high. The relative and absolute amounts of NK cells and of CD56(dim) and CD56(bright) NK cell subpopulations in patients with a normal baseline did not change under treatment. However, patients with a low baseline of NK cells and CD56(dim) NK cells showed a significant increase in these immune cell subsets, but the amounts remained to be lower than the normal baseline. The amount of CD56(bright) NK cells was unaffected by treatment. The baseline levels of NK cells were correlated with the number of metastatic organs. Their proportion increased, whereas the expression of NKG2D decreased significantly when more than one organ was affected by metastases. Low baseline levels of NK cells and CD56(dim) NK cells as well as normal baseline levels of CD56(bright) NK cells correlated significantly with a positive response to ipilimumab but not to pembrolizumab. Survival curves of patients with low amounts of CD56(dim) NK cells treated with ipilimumab showed a trend to longer survival. Normal baseline levels of CD56(bright) NK cells were significantly correlated with longer survival as compared to patients with high baseline levels. In conclusion, analysis of the amounts of total NK cells and of CD56(dim) and CD56(bright) NK cells subpopulations at baseline may help to predict the outcome of treatment with ipilimumab.