Immune System Evasion as Hallmark of Melanoma Progression: The Role of Dendritic Cells

Abstract

Melanoma is an immunogenic tumor whose relationship with immune cells resident in the microenvironment significantly influences cancer cell proliferation, progression, and metastasis. During melanomagenesis, both immune and melanoma cells undergo the immunoediting process that includes interconnected phases as elimination, equilibrium, and escape or immune evasion. In this context, dendritic cells (DCs) are active players that indirectly counteract the proliferation of melanoma cells. Moreover, DC maturation, migration, and cross-priming as well as their functional interplay with cytotoxic T-cells through ligands of immune checkpoint receptors result impaired. A number of signals propagated by highly proliferating melanoma cells and accessory cells as T-cells, natural killer cells (NKs), tumor-associated macrophages (TAMs), T-regulatory cells (T-regs), myeloid-derived suppressor cells (MDSCs), and endothelial cells participate to create an immunosuppressive milieu that results engulfed of tolerogenic factors and interleukins (IL) as IL-6 and IL-10. To underline the role of the immune infiltrate in blocking the melanoma progression, it has been described that the composition, density, and distribution of cytotoxic T-cells in the surrounding stroma is predictive of responsiveness to immunotherapy. Here, we review the major mechanisms implicated in melanoma progression, focusing on the role of DCs.

Keywords: T-cells; checkpoint inhibitors; dendritic cells; melanoma; microenvironment.

Figure 1

Inflamed vs. non-inflamed tumor microenvironment. The melanoma microenvironment consists of a complex immune infiltrate consisting of dendritic cells (DCs), CD8⁺ T-cells, natural killer cells (NKs), regulatory T-cells (Treg), myeloid-derived suppressor cells (MDSCs), cytokines, enzymes, and negative modulators. Apart from melanoma cells characterized by the loss of HLA-I expression and thus already capable of evading the immune system control, the infiltrate assumes three different phenotypes: inflamed (red), immune-excluded (violet), and the immune desert (blue), depending on whether its features contribute to overcoming or supporting anti-tumor immunity control. Tumors with an immune-inflamed profile are highly responsive to immunotherapy but their rich immune infiltrate includes dysfunctional T-cells exhausted by chronic antigen exposure. Immune-excluded tumors are characterized by a pre-existing anti-melanoma response and specific stromal-based inhibition whereas immune-desert tumors are immunologically “ignorant,” as T-cells rarely reach the tumor parenchyma or stroma. Melanoma cells, DCs and T-cells cross-talk through inhibitory or activating receptors, by which the immune response is induced or restrained, thus creating an equilibrium aimed at limiting melanoma cell proliferation and metastasis. MHC, major histocompatibility complex; CTLA-4, cytotoxic T-Lymphocyte antigen 4; PD-1, programmed death-1; PD-L1/2, programmed death-ligand 1/2; IDO, indoleamine 2,3-dioxygenase; TIM3, T-cell immunoglobulin mucin 3; LAG3, lymphocyte-activation gene 3; TIGIT, T cell Ig and ITIM domain; VISTA, V-domain Ig suppressor of T cell activation; TCR, T-cell receptor; MDSC, myeloid-derived suppressor cell; Treg, regulatory T cell; VEGF, vascular endothelial growth factor; IL, interleukin; CXCL, C-X-C motif ligand; GITR, glucocorticoid-induced TNFR-related protein; HVEM, herpes virus entry mediator; RANK, receptor activator of nuclear factor kappa-B.

Figure 2

Target therapy restores the immune system activity in melanoma microenvironment. (A) Melanoma microenvironment is characterized by the paucity of cytotoxic T-cells and the prevalence of immune suppressive cells (e.g., Treg and MDSC) and soluble factors (e.g., interleukins) that favor the tumor progression. Also, DCs are blocked at an immature stage, thus resulting unable to properly present and process tumor-derived antigens to immune competent populations. (B) BRAF/MEK inhibitors exert direct anti-melanoma activity and restore the tumor immunogenicity within the microenvironment. As effect of targeted therapy, melanoma cells undergo to apoptosis, release neo-antigens, and hamper the immunosuppressive signals, thus restoring antigen presentation by DCs and T-cell mediated cytotoxicity. In addition, MHC-I is re-activated and both T-cells and NK cells are recruited nearby tumor, while Tregs and MDSC become impaired.