Innate Immune Cells in Melanoma: Implications for Immunotherapy

Abstract

The innate immune system, composed of neutrophils, basophils, eosinophils, myeloid-derived suppressor cells (MDSCs), macrophages, dendritic cells (DCs), mast cells (MCs), and innate lymphoid cells (ILCs), is the first line of defense. Growing evidence demonstrates the crucial role of innate immunity in tumor initiation and progression. Several studies support the idea that innate immunity, through the release of pro- and/or anti-inflammatory cytokines and tumor growth factors, plays a significant role in the pathogenesis, progression, and prognosis of cutaneous malignant melanoma (MM). Cutaneous melanoma is the most common skin cancer, with an incidence that rapidly increased in recent decades. Melanoma is a highly immunogenic tumor, due to its high mutational burden. The metastatic form retains a high mortality. The advent of immunotherapy revolutionized the therapeutic approach to this tumor and significantly ameliorated the patients' clinical outcome. In this review, we will recapitulate the multiple roles of innate immune cells in melanoma and the related implications for immunotherapy.

Keywords: dendritic cells; immune checkpoint inhibitors; immunotherapy; macrophages; melanoma; monocytes; neutrophils; neutrophils extracellular traps; tumor microenvironment.

Figure 1

Melanoma is a malignant tumor, which develops from an alteration in epidermal melanocytes. One of the main risk factors is overall lifetime exposure to solar light and sunburn frequency. Unprotected exposure to UVA and UVB rays damages the DNA of skin cells, causing genetic defects or mutations that can lead to skin cancer and premature aging (a). Increasing data suggest that innate immunity has a role in affecting the tumor microenvironment (TME) and cancer patients’ clinical outcomes. Innate immune cells exhibit amazing adaptability, acquiring both pro- and anti-tumorigenic roles depending on different factors present in the TME (b). The primary treatment option for cutaneous melanoma is surgery. Among the treatments used against melanoma, it is also possible to find chemotherapy and radiotherapy. Melanoma cells are particularly sensitive to radiation. Until a few years ago, chemotherapy was the only weapon available in advanced disease but, today, it plays a minor role. In recent years, targeted and immunotherapies have shown promise in treating advanced melanomas. Despite these considerable gains, most people become resistant. Understanding the methods by which melanomas gain resistance is critical for developing customized medicines that take into account each patient’s unique genetic and immunological features (c).

Figure 2

The innate immune system, composed of MDSCs, macrophages, neutrophils, DCs, MCs, basophils, eosinophils, and ILCs, is the first line of defense. Innate immune cells are characterized by a surprising plasticity and can release both pro- and antitumorigenic molecules depending on factors present in the TME. Arrows indicate protumorigenic (red ones) or antitumorigenic (green ones) effects and molecules produced by melanoma or innate immune cells within the TME.

Figure 3

Immune cells respond to different immunogens in a dynamic and specialized manner because of their developmental diversity and phenotypic flexibility. Patrolling monocytes increase NK cell resistance to metastasis by releasing IL-15, which induces IFN-γ production. They also maintain NK cell activation by maintaining high levels of NK-cell-activating receptors and low levels of NK cell inhibitory receptors. Macrophages can activate and recruit NK cells, thus increasing their resistance to metastases. Neutrophils release neutrophils extracellular traps (NETs), which prevents the migration of tumor cells and promotes cytotoxicity towards neoplastic cells. Additionally, neutrophils promote metastasis by preventing NK cell activation basophils and eosinophils can produce various protumor signals through the release of angiogenic molecules such as vascular endothelial growth factor (VEGF) A and B. Eosinophils also display antitumorigenic activity. MDSCs are essential for the development of tumors. The interaction of CCL5 with CCR5 stimulates the growth, invasion, angiogenesis, and recruitment of immune cells into the TME. The known mediators of the immunosuppressive actions of MDSC are ARG-1, ROS, PD-L1, and NO. MCs can also produce a range of cytokines, such as TNF-α, IL-1, IL-4, IL-8, IL-6, MCP-3, and MCP-4, which can help suppress the growth of tumors by triggering apoptosis. Tumor vascularization can be promoted by MCs by the secretion of angiogenic molecules such as VEGF-A, IL-8, FGF-2, VEGF-C, MMP-2, and MMP-9.

Figure 4

ILC and DCs cross-talk in melanoma microenvironment. Proinflammatory cytokines expressed by DCs trigger the production of PDGF and GM-CSF by ILC1 cells, which, in turn, promotes tumor angiogenesis. ILC2 induces the recruitment of eosinophils to the lung metastatic niche, through the production of IL-5. Melanoma secretes IL-12, which causes endothelial cells to upregulate ICAM and VCAM, thus attracting NKp46+ ILC3 to the tumor bed and activating the vasculature. By promoting leukocyte infiltration through endothelial activation, NKp46+ ILC3 act against melanoma. Melanoma secreting CCL21 attracts CCR6⁺ (CD4⁺) ILC3, which interact with fibroblastic reticular cells (FRC) to produce lymphoid-like stroma, generating a tolerogenic tumor environment. ILC3 are activated by DC-derived IL-23, through the expression of RORγt. Thus, when DC-derived IL-23 is produced in the melanoma microenvironment, ILC3s are activated and contribute to the protection against melanoma.