Innate Lymphoid Cells in the Malignant Melanoma Microenvironment

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.

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

“…In cutaneous melanoma, there is an enrichment of NK, ILC1, and ILC3NCR + cells. Moreover, NK cells and ILC3 were increased in liver and lung metastases, and ILC2 was increased in lung metastases [ 33 ]. In melanoma patients, the dynamic differentiation of ILCs in the tumor environment may allow circulation of other ILC subsets [ 26 ].…”

“…The downregulation of activation receptors on the CD56 + CD16 + NK subsets from metastatic melanoma patients confirmed previously described numerous studies [ 34 ], including ours [ 35 , 36 ] on monitoring NK cells. Immunosuppressive factors and cytokines that are produced by the tumor as soluble molecules or presented on extracellular vesicles (EVs) may contribute to these immune defects of ILCs [ 33 ]. Furthermore, NK-derived extracellular vesicles can compromise NK cell function [ 37 ].…”

“…In several reports on lung metastasis models, IL-33-activated ILC2s were shown to mediate a potent immunosuppression of NK cells, promoting metastasis [ 50 , 51 ]. On the other hand, ILC2s were reported to amplify the antitumor effect of PD-1 blockades by activating tumor-specific T cells in an orthotopic murine model of pancreatic tumors [ 52 ], emphasizing the requirement for characterization of intra-tumoral ILC populations [ 33 ].…”

“…Overall, the immune checkpoint inhibitors that alter the tumor microenvironment change the crosstalk between resident ILCs, leading to anti- or pro-tumoral responses [ 33 ]. Our studies identify innate immunity parameters in the blood melanoma patients that are correlated with a response to immunotherapy.…”

Why Target Innate Immune Cells in Cancers?

“…All innate immune cells inside the TME can be involved in processes favoring tumor cell survival, proliferation, motility and invasive potential, resistance to treatment and to immune attacks, epithelial-mesenchymal transition, and angiogenesis. However, the mechanisms of these processes can differ according to the immune cell considered, to the tissue, and to the stage of the tumor [3][4][5]. These diverse mechanisms can involve cell-cell interactions via different membrane molecules at the surface of immune cells and cancer cells.…”