Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

Abstract

Several studies have reported that cellular and soluble components of the tumor microenvironment (TME) play a key role in cancer-initiation and progression. Considering the relevance and the complexity of TME in cancer biology, recent research has focused on the investigation of the TME content, in terms of players and informational exchange. Understanding the crosstalk between tumor and non-tumor cells is crucial to design more beneficial anti-cancer therapeutic strategies. Malignant pleural mesothelioma (MPM) is a complex and heterogenous tumor mainly caused by asbestos exposure with few treatment options and low life expectancy after standard therapy. MPM leukocyte infiltration is rich in macrophages. Given the failure of macrophages to eliminate asbestos fibers, these immune cells accumulate in pleural cavity leading to the establishment of a unique inflammatory environment and to the malignant transformation of mesothelial cells. In this inflammatory landscape, stromal and immune cells play a driven role to support tumor development and progression via a bidirectional communication with tumor cells. Characterization of the MPM microenvironment (MPM-ME) may be useful to understand the complexity of mesothelioma biology, such as to identify new molecular druggable targets, with the aim to improve the outcome of the disease. In this review, we summarize the known evidence about the MPM-ME network, including its prognostic and therapeutic relevance.

Keywords: cancer stem cells; inflammation; macrophages; mesothelioma; tumor microenvironment.

Figure 2

Cellular and soluble factors in MPM-ME. The interconnection between tumor cells and the surrounding stromal and immune component is necessary to create a permissive environment for cancer growth, immune escape and invasiveness [59]. Tumor cells, by the release of the growth factors FGF-2 and PDGF-AA, recruited fibroblast at tumor sites promoting their pro-tumoral activity as CAFs. In turn, these CAFs secreted the HGFs, produced ECM-related proteins, expressed the CTGF and other cytokines supporting tumor growth [65,66]. Additionally, MPM cells have been found to express the CTGF as modulator of ECM-related proteins and supporter of cancer invasiveness [62]. CAFs as well as tumor cells, via the release of the angiogenic VEGF, promoted the recruitment of endothelial cells and the vasculogenesis [67,69,70]. Exhausted Th and CD8⁺ T cells are also present in TME, characterized by the expression of immune checkpoint molecules, such as PD-1, TIM3, LAG3 [72]. Moreover, PD-L1 signaling induced Th cells reprogramming in Treg cells [73]. Moreover, the NK cells showed an immunosuppressive phenotype and low cytotoxicity [77]. TAMs, which represent the most abundant immune population [36], are recruited at tumor sites by tumor-produced CCL2 [92]. MPM cells enhance the malignancy of macrophages via the release of TGF-β, IL-10, exosomes (EVs) and M-CSF [36]. The presence of M-CSF and IL-34 was associated with short survival and chemoresistance [98,99]. Recently, the inhibition of CSF-1R has been shown to reduce mesothelioma progression and increase the susceptibility of MPM to immune checkpoint inhibitors [101]. The activation of the IL-1β/IL-1R signaling pathway in tumors by TAMs is correlated with the acquisition of a CSC-like phenotype [96]. As observed in other tumor types, adenosine (ADO) pathways may be involved in MM cells-TAMs interaction, inducing the release of pro-tumoral cytokines and promoting TAMs proliferation [115,127,128]. Although limited data indicate its involvement in MPM immunosuppression [117], a deep investigation is required. This figure was prepared using a template on the Servier medical art website (http://smart.servier.com/).

Figure 1

BAP1 loss and microenvironment in human mesothelioma. Hematoxylin and eosin stain and a set of immunostainings performed on formalin-fixed paraffin-embedded sections of two cases of human epithelioid mesothelioma of the pleura showing loss of BAP1. The upper case (A–F) results massively infiltrated by CD163⁺ macrophages, SMA⁺ fibroblasts and CD3⁺ T-cells including the FOXP3⁺ regulatory population, whereas the bottom case (G–L) displays a scant macrophage infiltration. Primary antibodies included broad-spectrum cytokeratin (CK, B) or cytokeratin 5/6 (H) as mesothelioma markers; anti-BAP1 (C,I); CD163 (D,J), for tumor-associated macrophages (TAMs); smooth muscle actin (SMA, E,K) for cancer-associated fibroblasts (CAFs); CD3 (F,L) for T-cells and FoxP3 for regulatory T-cells. Arrows (F,L) highlight representative regulatory T-cells. Original magnification 400×, scale bar 50 μM.