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

Costanza Maria Cristiani,Ennio Carbone,Mariaelena Capone,Vito Vanella,Giuseppe Viglietto,Gabriele Madonna,Hergen Spits,Daniela Patrizia Foti,Marilena Tuffanelli,Cinzia Garofalo,Paolo Antonio Ascierto,Domenico Mallardo,Marta Greco

doi:10.3389/fimmu.2022.811131

Abstract

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 TNFα 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 TNFα, 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 TNFα 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.

Highlights

Innate lymphoid cells (ILCs) are a heterogeneous family of lymphocytes representing the innate counterpart of T cells and are involved in immune responses as well as in tissue development and homeostasis
The three main innate lymphoid cells (ILCs) subsets exhibited altered proportions compared to healthy donors, with lower percentages of CD117+ ILC2s and CD117+ ILCs, which are mostly composed of precursor committed to ILC3s and include more mature ILC3s [3, 4], and higher frequencies of
To investigate the modifications in ILC subset frequencies that could occur in stage IV melanoma patients during immune checkpoint inhibitors (ICIs) therapies, we analyzed patients treated with Ipilimumab (8 patients) or Nivolumab (24 patients) separately

Summary

Introduction

Innate lymphoid cells (ILCs) are a heterogeneous family of lymphocytes representing the innate counterpart of T cells and are involved in immune responses as well as in tissue development and homeostasis. ILC3s resemble Th17 cells, expressing RORgt and producing IL-17 and IL-22, and are involved in the immune response against extracellular microbes. NKp44 (NCR2) expression distinguishes two subsets of ILC3s, with NKp44ILC3s mainly producing IL-17, while IL-22 secretion is restricted to NKp44+ ILC3s. CD117 distinguishes ILC2s in two subsets: CD117- ILC2s are considered to be a more mature and lineage-committed subpopulation, expressing high levels of GATA3 and secreting large amounts of type 2 cytokines; on the other hand, CD117+ ILC2s are more plastic and share some features with ILC3s, including RORgt expression and capability to produce IL-17 [5, 6]

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Conclusion