Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is a rare and fatal disease of the pleural lining. Up to 80% of the MPM cases are linked to asbestos exposure. Even though its use has been banned in the industrialized countries, the cases continue to increase. MPM is a lethal cancer, with very little survival improvements in the last years, mirroring very limited therapeutic advances. Platinum-based chemotherapy in combination with pemetrexed and surgery are the standard of care, but prognosis is still unacceptably poor with median overall survival of approximately 12 months. The genomic landscape of MPM has been widely characterized showing a low mutational burden and the impairment of tumor suppressor genes. Among them, BAP1 and BLM are present as a germline inactivation in a small subset of patients and increases predisposition to tumorigenesis. Other studies have demonstrated a high frequency of mutations in DNA repair genes. Many therapy approaches targeting these alterations have emerged and are under evaluation in the clinic. High-throughput technologies have allowed the detection of more complex molecular events, like chromotripsis and revealed different transcriptional programs for each histological subtype. Transcriptional analysis has also paved the way to the study of tumor-infiltrating cells, thus shedding lights on the crosstalk between tumor cells and the microenvironment. The tumor microenvironment of MPM is indeed crucial for the pathogenesis and outcome of this disease; it is characterized by an inflammatory response to asbestos exposure, involving a variety of chemokines and suppressive immune cells such as M2-like macrophages and regulatory T cells. Another important feature of MPM is the dysregulation of microRNA expression, being frequently linked to cancer development and drug resistance. This review will give a detailed overview of all the above mentioned features of MPM in order to improve the understanding of this disease and the development of new therapeutic strategies.

Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

“…A link between high density of CD8 + immune cells and improved MPM patient outcomes has also been demonstrated [ 71 , 75 , 76 ], suggesting a potential therapeutic strategy. Natural killer (NK) cells were also present in MPM samples; however, these cells showed an immunosuppressive profile and lower cytotoxic functions [ 77 ]. Given the heterogeneity of immune cell content in MM TME and the pro-tumor functions of the stromal content, an understanding of these components is required for better understanding MM pathogenesis and for the development of an efficacious anti-cancer targeted therapy.…”

“…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 ].…”

The Epithelial-to-Mesenchymal Transition (EMT) in the Development and Metastasis of Malignant Pleural Mesothelioma

“…Moreover, asbestos exposure induces the release of different molecules, such as growth factors or cytokines (such as, TGFβ, HGF and VEGF), which are widely involved in asbestos-related pathologies onset. These asbestos-induced mechanisms promote cell necrosis and the release of damage-associated molecular patterns (DAMPs), such as high mobility group box 1 protein (HMGB1) involved in survival, proliferation and autophagy, particularly in mesothelial asbestos-exposed cells [8,19]. Therefore, asbestos fibers were demonstrated to allow, through these events, the creation of a microenvironment prone to the cancer onset and progression.…”

Novel and Future Treatment Options in Mesothelioma: A Systematic Review

“…TNF-α released by macrophages activates the NF-κB signaling pathway in mesothelial cells and supports their survival when exposed to asbestos. Therefore, TNF-α and IL-1β are important players mediating mesothelioma malignant transformation and progression [5].…”

“…For example, overexpression of hsa-miR-29c* resulted in a significant decrease in proliferation and migration in mesothelioma cell lines. Therefore, overexpression of hsa-miR-29c* could impact a more favorable prognosis in epithelioid mesothelioma patients [5,6]. Furthermore, cell cycle regulation can influence the progression of mesothelioma.…”