Tumor Microenvironment: Implications in Melanoma Resistance to Targeted Therapy and Immunotherapy

Abstract

Antitumor therapies have made great strides in recent decades. Chemotherapy, aggressive and unable to discriminate cancer from healthy cells, has given way to personalized treatments that, recognizing and blocking specific molecular targets, have paved the way for targeted and effective therapies. Melanoma was one of the first tumor types to benefit from this new care frontier by introducing specific inhibitors for v-Raf murine sarcoma viral oncogene homolog B (BRAF), mitogen-activated protein kinase (MEK), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), and, recently, immunotherapy. However, despite the progress made in the melanoma treatment, primary and/or acquired drug resistance remains an unresolved problem. The molecular dynamics that promote this phenomenon are very complex but several studies have shown that the tumor microenvironment (TME) plays, certainly, a key role. In this review, we will describe the new melanoma treatment approaches and we will analyze the mechanisms by which TME promotes resistance to targeted therapy and immunotherapy.

Keywords: immunotherapy; melanoma; targeted therapy; therapeutic resistance; tumor microenvironment.

Figure 1

Schematic representation of the most important approaches to melanoma treatment. (A) Mitogen-activated protein kinase (MAPK) signaling is often deregulated in melanoma and, for this reason, several drugs against the components of the pathway have been developed. Although less frequently mutated, the v-kit Hardy–Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) receptor tyrosine kinase, represents another molecular target for certain melanomas, and KIT inhibitors can be used in combination with chemotherapy or immunotherapy. (B) Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), interacting with B7 ligands present on the surface of dendritic cells (DCs), prevents the activation of T lymphocytes. The functional block of CTLA-4 mediated by monoclonal antibodies supports the interaction between B7 ligands and CD28, positive regulator receptor of the T lymphocyte activity. (C) Melanoma cells usually express elevated levels of programmed death ligand (PDL) 1 and 2, which, through interaction with programmed cell death protein 1 (PD-1) receptor on T cells, block their activation. Pharmacological inhibition of the PD-1 axis restores T cells’ ability to recognize and kill tumor cells.

Figure 2

Relationship between melanoma and tumor microenvironment (TME). In this figure, is illustrated schematically the reciprocal interactions between melanoma cells and the other components of TME. Melanoma’s TME, involved in tumor growth, progression, and drug resistance, is essentially represented by regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), cluster differentiation (CD) 4⁺/CD8⁺ lymphocytes, dendritic cells (DCs), endothelial and lymphatic cells, and extracellular matrix (ECM).

Figure 3

Melanoma/CAFs’ paracrine interconnections. (A–E) In this figure, is illustrated schematically the mutual interactions between melanoma cells and cancer-associated fibroblasts (CAFs). Several factors are implicated in these intricate interconnections at the basis of drugs resistance: Tumor necrosis factor receptor-associated factor 6 (TRAF6), fibroblast growth factor 19 (FGF19), metalloproteinases 2 and 9 (MMP2 and MMP9), hepatocyte growth factor (HGF), neuregulin 1 (NRG1), V-erb-b2 avian erythroblastic leukemia viral oncogene homolog3 (ErbB3), transforming growth factor β (TGF-β), reactive oxygen species (ROS), CXC motif chemokine 5 (CXCL5), programmed death-ligand 1 (PDL-1).