Innate Lymphoid Cells in the Malignant Melanoma Microenvironment

SIMPLE SUMMARY: Innate lymphoid cells (ILCs) are the innate counterparts of adaptive immune cells. Emerging data indicate that they are also key players in the progression of multiple tumors. In this review we briefly describe ILCs’ functions in the skin, lungs and liver. Next, we analyze the role of ILCs in primary cutaneous melanoma and in its most frequent and deadly metastases, those in liver and lung. We focus on their dual anti– and pro-tumoral functions, depending on the cross-interactions among them and with the surrounding stromal cells that form the tumor microenvironment (TME) in each organ. Next, we detail the role of extracellular vesicles secreted to the TME by ILCs and melanoma on both cell populations. We conclude that the identification of markers and tools to allow the modulation of individual ILC subsets, in addition to the development of standardized protocols, is essential for addressing the therapeutic modulation of ILCs. ABSTRACT: The role of innate lymphoid cells (ILCs) in cancer progression has been uncovered in recent years. ILCs are classified as Type 1, Type 2, and Type 3 ILCs, which are characterized by the transcription factors necessary for their development and the cytokines and chemokines they produce. ILCs are a highly heterogeneous cell population, showing both anti– and protumoral properties and capable of adapting their phenotypes and functions depending on the signals they receive from their surrounding environment. ILCs are considered the innate counterparts of the adaptive immune cells during physiological and pathological processes, including cancer, and as such, ILC subsets reflect different types of T cells. In cancer, each ILC subset plays a crucial role, not only in innate immunity but also as regulators of the tumor microenvironment. ILCs’ interplay with other immune and stromal cells in the metastatic microenvironment further dictates and influences this dichotomy, further strengthening the seed-and-soil theory and supporting the formation of more suitable and organ-specific metastatic environments. Here, we review the present knowledge on the different ILC subsets, focusing on their interplay with components of the tumor environment during the development of primary melanoma as well as on metastatic progression to organs, such as the liver or lung.