Immune system and melanoma biology: a balance between immunosurveillance and immune escape

Abstract

Melanoma is one of the most immunogenic tumors and its relationship with host immune system is currently under investigation. Many immunomodulatory mechanisms, favoring melanomagenesis and progression, have been described to interfere with the disablement of melanoma recognition and attack by immune cells resulting in immune resistance and immunosuppression. This knowledge produced therapeutic advantages, such as immunotherapy, aiming to overcome the immune evasion. Here, we review the current advances in cancer immunoediting and focus on melanoma immunology, which involves a dynamic interplay between melanoma and immune system, as well as on effects of "targeted therapies" on tumor microenvironment for combination strategies.

Keywords: immune escape; immune system; immunoediting; immunogenicity; melanoma.

Figure 1. CTLA4 and PD1 regulate different stages of T-cell response

(A) T cell activation requires two complementary signals. The interaction between TCR and peptide-MHC complex must be associated by a second co-stimulatory signal mediated by CD28. Conversely the binding of CTLA4 to B7-1/2 (CD80/86) provides a control signal that suppresses ongoing T-cell activation. (B) PD1 is upregulated on T cells after persistent antigen exposure. When PD1 binds its ligand as PDL1 and PDL2 expressed by tumor cells, the T cell receives on inhibitory signal. Antibodies direct to CTLA4 or PD1/PDL1 can activate T cells by preventing their functional disablement. Abbreviations: DC, dendritic cell; CTLA4, cytotoxic T lymphocyte antigen 4; PD1, programmed death 1; TCR, T-cell receptor; MHC, major histocompatibility complex; PD-L1, programmed death ligand 1; PD-L2, programmed death-ligand 2.

Figure 2. Targeted therapy affects the tumor microenvironment in favour of immune re-activation

Left: Melanoma progression includes many pathogenetic and molecular events which contribute to the ineffective anti-tumor immunity. Melanoma microenvironment is enriched of immune-suppressive cytokines (e.g., IL-10, IL-6; TGF-β and VEGF) that drive the infiltration of immunosuppressive cells (e.g. Treg and MDSC), while impair the antigen processing machinery by DCs and the anti-tumor effect by T-cells and NK cells. Right: BRAF/MEK inhibitors exert direct anti-melanoma activity and restore the tumor immunogenicity within the microenvironment. Particularly, the targeted therapy induces the production of melanoma specific neo-antigens and hampers the immunosuppressive signals, thus restoring antigen presentation by DCs and T-cell mediated cytotoxicity. As a consequence, T-cells and NK cells increase nearby tumor, while Tregs and MDSC are strongly impaired. In addition, BRAF inhibitors may also condition tumor microenvironment in support of immunotherapy by inducing the expression of effector cell exhaustion molecules (e.g. PD-1 and TIM-3) on immune cells or PD-L1 on tumor cells.