Specific Patterns of Blood ILCs in Metastatic Melanoma Patients and Their Modulations in Response to Immunotherapy.

Louise Rethacker,Eve Maubec,Anne Caignard,Claudia Bejar,Hélène Moins-Teisserenc,Marie Roelens

doi:10.3390/cancers13061446

Abstract

Simple SummaryAnti-CTLA-4 and anti-PD-1 immune checkpoints inhibitors (ICI) have revolutionized the treatment of metastatic melanoma patients, leading to durable responses. However, some patients still not respond to this clinically used immunotherapies and there is a lack of biomarkers leading to the choice of first-line therapies. Innate lymphoid cells (ILC) express immune checkpoint receptors and are involved in anti-melanoma immune response. The aim of this article is to study ILCs from peripheral blood of melanoma patients receiving Ipilimumab, an anti-CTLA-4 treatment, and their association with clinical responses to this therapy. Our results show an impact of Ipilimumab on ILCs proportions and phenotype in blood. Moreover, the presence of anergic CD56dimCD16−DNAM-1− NK cells were associated with progression of the disease. These findings demonstrate the important role of ILC in the response to ICI.Immunotherapy targeting immune checkpoint receptors brought a breakthrough in the treatment of metastatic melanoma patients. However, a number of patients still resist these immunotherapies. Present on CD8+T cells, immune checkpoint receptors are expressed by innate lymphoid cells (ILCs), which may contribute to the clinical response. ILCs are composed of natural killer (NK) cells, which are cytotoxic effectors involved in tumor immunosurveillance. NK cell activation is regulated by a balance between activating receptors that detect stress molecules on tumor cells and HLA-I-specific inhibitory receptors. Helper ILCs (h-ILCs) are newly characterized ILCs that secrete cytokines and regulate the immune homeostasis of tissue. We investigated the modulation of blood ILCs in melanoma patients treated with ipilimumab. Circulating ILCs from metastatic stage IV melanoma patients and healthy donors were studied for their complete phenotypic status. Patients were studied before and at 3, 6, and 12 weeks of ipilimumab treatment. A comparison of blood ILC populations from donors and melanoma patients before treatment showed changes in proportions of ILC subsets, and a significant inverse correlation of CD56dim NK cells and h-ILC subsets was identified in patients. During treatment with ipilimumab, percentages of all ILC subsets were reduced. Ipilimumab also impacted the expression of the CD96/TIGIT/DNAM-1 pathway in all ILCs and increased CD161 and CTLA-4 expression by h-ILCs. When considering the response to the treatment, patients without disease control were characterized by higher percentages of CD56bright NK cells and ILC1. Patients with disease control displayed larger populations of activated CD56dimCD16+ DNAM-1+ NK cells, while anergic CD56dimCD16−DNAM-1− NK cells were prominent in patients without disease control. These results provide original findings on the distribution of ILC subsets in advanced melanoma patients and their modulation through immunotherapy. The effects of ipilimumab on these ILC subsets may critically influence therapeutic outcomes. These data indicate the importance of considering these innate cell subsets in immunotherapeutic strategies for melanoma patients.

Highlights

Melanomas are highly metastatic tumors for which the first-line treatment is immunotherapy
Among the h-innate lymphoid cells (ILCs), which represented 2 to 12% of the CD7+ cells, there was a major subset of ILC1 (2 to 6%) and 2–4% of ILC2; ILC3 cells were rare
There was a trend of increasing percentages of ILC2 in patients compared to donors (Figure 1B)

Summary

Introduction

Melanomas are highly metastatic tumors for which the first-line treatment is immunotherapy. Natural killer (NK) cells are potent cytolytic effectors that play a role in the innate and adaptive antitumor immune responses. NK cells are endowed with the capacity to kill tumor cells without prior sensitization, and NK cells are supress considered highly sophisticated detectives of harmful changes in cells themselves and are pivotal catalyzers of adaptive T cell responses [6,7]. NK cells are considered the major source of IFNγ in vivo, and NK-derived IFNγ is crucial for priming T helper 1 responses [8]. NK cells originate from bone marrow and maturate in the lymph nodes. Though they mainly circulate, NK cells infiltrate lymphoid organs and tissue by migrating through blood and lymphatics

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