Helper Innate Lymphoid Cells—Unappreciated Players in Melanoma Therapy

SIMPLE SUMMARY: Helper innate lymphoid cells (ILCs) represent the innate counterpart of helper T lymphocytes. Increasing findings indicate that they are involved in the pathogenesis and progression of solid tumors. In this review, we describe the alterations induced by the melanoma tumor microenvironment (TME) in helper ILCs, as well as their capability to respond to melanoma cells and shape the TME in turn. Next, we provide details about the expression and function of checkpoint receptors on helper ILCs and how therapy with immune checkpoint inhibitors may modulate their activation and properties. We also describe how the immunomodulatory properties of targeted therapy used to treat melanoma may affect helper ILC function. We conclude by discussing the limits of the current knowledge about helper ILC roles in metastatic melanoma disease, as well as the challenges that need to be addressed to clarify their contribution to pathophysiology and therapy. ABSTRACT: Immune checkpoint inhibitors (ICIs) and targeted therapy have dramatically changed the outcome of metastatic melanoma patients. Although immune checkpoints were developed based on the biology of adaptive T cells, they have subsequently been shown to be expressed by other subsets of immune cells. Similarly, the immunomodulatory properties of targeted therapy have been studied primarily with respect to T lymphocytes, but other subsets of immune cells could be affected. Innate lymphoid cells (ILCs) are considered the innate counterpart of T lymphocytes and include cytotoxic natural killer cells, as well as three helper subsets, ILC1, ILC2 and ILC3. Thanks to their tissue distribution and their ability to respond rapidly to environmental stimuli, ILCs play a central role in shaping immunity. While the role of NK cells in melanoma physiopathology and therapy is well established, little is known about the other helper ILC subsets. In this review, we summarize recent findings on the ability of the melanoma TME to influence the phenotype and functional plasticity of helper ILCs and highlight how this subset may in turn shape the TME. We also discuss changes in the melanoma TME induced by targeted therapy that could affect helper ILC functions, the expression of immune checkpoints on this subset and how their inhibition by ICIs may modulate helper ILC function and contribute to therapeutic efficacy.