Influence of Tumor Microenvironment and Fibroblast Population Plasticity on Melanoma Growth, Therapy Resistance and Immunoescape

Abstract

Cutaneous melanoma (CM) tissue represents a network constituted by cancer cells and tumor microenvironment (TME). A key feature of CM is the high structural and cellular plasticity of TME, allowing its evolution with disease and adaptation to cancer cell and environmental alterations. In particular, during melanoma development and progression each component of TME by interacting with each other and with cancer cells is subjected to dramatic structural and cellular modifications. These alterations affect extracellular matrix (ECM) remodelling, phenotypic profile of stromal cells, cancer growth and therapeutic response. The stromal fibroblast populations of the TME include normal fibroblasts and melanoma-associated fibroblasts (MAFs) that are highly abundant and flexible cell types interacting with melanoma and stromal cells and differently influencing CM outcomes. The shift from the normal microenvironment to TME and from normal fibroblasts to MAFs deeply sustains CM growth. Hence, in this article we review the features of the normal microenvironment and TME and describe the phenotypic plasticity of normal dermal fibroblasts and MAFs, highlighting their roles in normal skin homeostasis and TME regulation. Moreover, we discuss the influence of MAFs and their secretory profiles on TME remodelling, melanoma progression, targeted therapy resistance and immunosurveillance, highlighting the cellular interactions, the signalling pathways and molecules involved in these processes.

Keywords: fibroblasts; melanoma; melanoma-associated fibroblasts; tumor microenvironment.

Figure 1

Schematic representation of the bidirectional interactions between normal fibroblasts or melanoma-associated fibroblasts (MAFs) and melanoma cells. The main soluble mediators involving in this crosstalk are reported. Normal fibroblasts can inhibit the growth of melanoma cells. IL-6/-15, TGF-β, PEDF, TNF-α, IFNγ and WFDC1 are produced by normal fibroblasts and associated with melanoma inhibition. Concurrently, normal fibroblasts are forced by melanoma cells to acquire a constitutively activated state and differentiate into the tumor-promoting MAFs. MAF differentiation occurs in the tumor mass through melanoma cell-derived soluble factors (such as TGF-β, IL-1β, PDGF, FGF, miR-155/-210/-211) or direct cell–cell contacts. In turn, MAFs secrete soluble mediators (such as pro-inflammatory proteins, MMPs, IL-6, HGF, etc.) leading to melanoma growth and progression. Of note, IL-6 and TGF-β act as tumor suppressors at early stage of melanoma and tumor promoters at late stage. Other conditions promoting MAF differentiation are represented by hypoxia and target therapies (such as MAPKi). Black T bar represents inhibition, while black arrows depict induction. The transition from normal fibroblasts to the tumor-promoting MAFs is indicated by the grey arrow.

Figure 2

Involvement of MAFs in melanoma growth and progression. Schematic representation of the principal MAF-derived molecules, including growth factors, cytokines, chemokines and proteases leading to extracellular matrix (ECM) remodelling, pharmacological resistance, and increased melanoma cell survival, proliferation, and migration. MAF-derived ECM is a functional and structural support network, enabling melanoma cells to proliferate, survive also during pharmacological treatment, migrate, and escape from the primary tumor site to colonize distant sites. ECM proteins produced by MAFs induce pro-survival, pro-proliferative, and pro-migratory signalling pathways in melanoma cells.

Figure 3

MAF immunomodulatory functions. MAFs generate an immunosuppressed melanoma microenvironment by multiple mechanisms. They increase the expression of various inflammatory and immunosuppressive factors, including TGF-β, IL-6, MMPs, PGE2, COX-2, CXCL5, and PDL1/2, which dramatically impair the anti-tumor activity of immune cells. Furthermore, MAFs alter the extracellular availability of lactate, glucose, and arginine, which are important immune-modulating metabolites involved in immune cell suppression or polarization toward a tumor-promoting phenotype. Consequently, the generation of an immunosuppressive, glucose- and arginine-poor, lactate-rich melanoma microenvironment allows melanoma cells to evade immune surveillance and thus survive and proliferate safely in the tumor mass.