Altered Frequencies and Functions of Innate Lymphoid Cells in Melanoma Patients Are Modulated by Immune Checkpoints Inhibitors

Monoclonal antibodies targeting immune checkpoints improved clinical outcome of patients with malignant melanoma. However, the mechanisms are not fully elucidated. Since immune check-point receptors are also expressed by helper innate lymphoid cells (ILCs), we investigated the capability of immune checkpoints inhibitors to modulate ILCs in metastatic melanoma patients as well as melanoma cells effects on ILC functions. Here, we demonstrated that, compared to healthy donors, patients showed a higher frequency of total peripheral ILCs, lower percentages of CD117(+) ILC2s and CD117(+) ILCs as well as higher frequencies of CD117(-) ILCs. Functionally, melanoma patients also displayed an impaired TNF alpha secretion by CD117(-) ILCs and CD117(+) ILCs. Nivolumab therapy reduced the frequency of total peripheral ILCs but increased the percentage of CD117(-) ILC2s and enhanced the capability of ILC2s and CD117(+) ILCs to secrete IL-13 and TNF alpha, respectively. Before Nivolumab therapy, high CCL2 serum levels were associated with longer Overall Survival and Progression Free Survival. After two months of treatment, CD117(-) ILC2s frequency as well as serum concentrations of IL-6, CXCL8 and VEGF negatively correlated with both the parameters. Moreover, melanoma cells boosted TNF alpha production in all ILC subsets and increased the number of IL-13 producing ILC2s in vitro. Our work shows for the first time that PD-1 blockade is able to affect ILCs proportions and functions in melanoma patients and that a specific subpopulation is associated with the therapy response.

Automated summary

Monoclonal antibodies targeting immune checkpoints have shown improved clinical outcomes for patients with malignant melanoma, but the underlying mechanisms are not fully understood. This study investigated the effects of immune checkpoint inhibitors on innate lymphoid cells (ILCs) and the impact of melanoma cells on ILC functions. The findings suggest that PD-1 blockade can affect the proportions and functions of ILCs in melanoma patients, and specific subpopulations are associated with treatment response.