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.

Keywords: genetic alterations; immunotherapy; mesothelioma; targeted therapy; tumor microenvironment.

Figure 1

Mechanisms of asbestos-induced carcinogenesis. Asbestos fibers reach the mesothelial cells where they can induce cell death and the release of inflammatory mediators such as HMGB1 and CCL2. The recruited macrophages are activated through HMGB1 binding to TLR4 and RAGE to induce TNF-α or by inflammasome activation through asbestos fibers. Activation of caspase-1 and cleavage of pro-IL-1β to the active form IL-1β can lead to further survival signals in mesothelial cells. HMGB1 can also bind to TLR4 and RAGE expressed on mesothelial cells supporting survival of those cells.

Figure 2

Tumor microenvironment in mesothelioma. Overview on the functionality and interactions of different immune cells studied in MPM patients. NK cells and T cells express inhibitory receptors such as TIM-3, LAG-3 and TIGIT and are influenced by a suppressive cytokines (PGE2, TGF-β) and the presence of Treg cells in performing their cytotoxic functions. Macrophages show a M2-like phenotype with expression of CD206 and CD163 on their surface. B cells in the TME produce specific antibodies against cancer cells, participating in the anti-tumor immune response.

Figure 3

Chromotripsis in mesothelioma. A defective mitosis process leads to the formation of micronuclei. Further replication leads to chromosome shattering and the addition of genetic material through the NHEJ. This process forms chromosome rearrangements that in MPM interest genes like RBFOX1, PARK2, PTPRD, CTNNA3 and ANK51B, and are linked to amplification of key MPM genes like NF2 and CDKN2A, or the loss of genetic material of BAP1 and KDM6A (113, 150, 151). Amplification of oncogenes due to chromotripsis has been recently associated with drug resistance (152). The extensive chromosomal breakage upon chromotripsis events leads to neoantigen presentation that can make cells more sensitive to immunotherapy (150).