Inflammation And Mesothelioma Development: Immunological Insights – Malignant mesothelioma is a rare and aggressive cancer that develops in the thin layer surrounding the mesothelium and is mainly caused by exposure to asbestos. Despite improvements in patients’ prognosis with conventional cancer treatments such as surgery, chemotherapy, and radiation therapy, there is no cure for advanced disease. New therapeutic possibilities have been sought in recent years. A better understanding of the mechanisms underlying dynamic tumor interactions with the immune system has led to the development of immunotherapeutic approaches. Several recent clinical trials have shown interest in developing effective treatments that can be used to combat the disease. Immune checkpoint inhibitors, oncolytic adenoviruses, and their combination represent a promising strategy that can be used synergistically to overcome immunosuppression in the mesothelial tumor microenvironment. This review provides a synthesized overview of the current state of knowledge regarding new treatment options for mesothelioma, focusing on the results of clinical trials conducted in this area.
Malignant pleural mesothelioma (MPM) is an aggressive and rare type of cancer that develops in the lining of the pleura, which consists of mesothelial cells (1, 2). It is considered an occupational disease because it is closely related to previous exposure to asbestos in the workplace. In fact, men who work in areas with high concentrations of this harmful substance tend to be more exposed than women who are less exposed to asbestos (3). The incidence of this cancer has increased steadily worldwide over the past decade, and the number of cases is predicted to increase in the coming period. The main reasons for this are the long time between the first exposure and the onset of the disease and the widespread use of asbestos in many industries in the 1970s (4). Despite today’s awareness of its dangers, asbestos is still widely used in industrialized countries such as India, Russia and Brazil. So this problem continues (1). Furthermore, exposure and accidental exposure to this material during the removal process from buildings is a serious material that will persist until it is banned worldwide (3). Unfortunately, malignancy is almost always fatal, with an average survival time from diagnosis of 9–12 months (3). The low chance of recovery is mainly related to the fact that the tumor has been dormant for a long time (up to 50 years), so when its presence is detected, it is too late to intervene and eliminate widespread malignancy (1, 2, 5). Although some treatments are currently available, they are not conclusive, but strong research is needed to give mesothelioma patients hope (6).
Inflammation And Mesothelioma Development: Immunological Insights
Here we focus on the current standards of care and future prospects for mesothelioma treatment. Data from current immunotherapy clinical trials are shedding light on this area, and significant changes in mesothelioma treatment may occur in the coming years. Therefore, in this review, we present the clinical perspectives of using oncolytic viruses in combination with immune checkpoint inhibitors (ICIs). We hope that this review will help the global community to design appropriate immune interventions for the treatment of mesothelioma.
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MPM is the result of neoplastic transformation of mesothelial cells, which form a thin monolayer that covers the entire surface of the pleura. This malignancy is mainly caused by inhalation of asbestos, with about 80% of cases related to previous exposure (7). Asbestos, a hazardous silicate mineral, occurs naturally in rocks and soil and can be divided into two categories based on shape: the serpentine type, which consists of serpentine fibers (called chrysotile), and the needle-shaped amphibole. The latter is divided into crocidolite, amosite, anthophyllite, tremolite and actinolite (8). The ability of this mineral to cause disease is related to the thickness and length of the fibers, as well as its weight and length of exposure. For example, the correlation between amphibole fiber exposure and MPM induction is well established. The long and thin shape of the bristles allows it to penetrate deep into the lungs. Crocidolite is considered the most carcinogenic form of asbestos (7). However, the etiology of the tumor is not fully understood and may be related to factors other than asbestos (9). New insights are being explored into other possible triggers, such as exposure to minerals with properties similar to asbestos and exposure to therapy or workplace radiation known to have carcinogenic effects. In addition, an oncogenic virus called simian virus 40 appears to play a role in mesothelium development, although results for this virus require further investigation (9). Several studies have shown that the virus can express the large T antigen (Tag), which activates pathways related to cell growth and survival (10). Among them, phosphatidylinositol 3-kinase (PI3K/Akt) is known to be involved in preventing apoptosis by disrupting the cell cycle and suppressing pro-apoptotic proteins, and has been shown to be a critical mechanism responsible for the evolution of malignant cells. (11). Thus, Cacciotti et al. demonstrated that SV40-related growth factors (i.e., VEGF) are released in the presence of asbestos fibers and induce Akt phosphorylation in mesothelial cells, leading to progressive resistance to apoptosis (10). This evidence, combined with exposure to toxic agents, may explain the potential co-carcinogenic properties of SV40. Therefore, chronic exposure to asbestos remains the main cause of MPM, and the shape and length of asbestos fibers determine the ability of particles to penetrate the lung epithelium (3). There they can cause damage in different ways. First, the fibers cause pleural irritation and a constant cycle of irritation, breakdown, and repair. This state of prolonged chronic inflammation leads to inflammation or tumor growth in the mesothelial cells (3). Another major consequence of asbestos exposure is the formation of reactive oxygen species (ROS), known for their toxicity and ability to cause DNA damage (3). The production of these dangerous free radicals is due to both the iron content of the asbestos fibers and the phagocytosis of macrophages (12), which are unable to be processed by scavenging cells, leading to excessive release of ROS (7). First, the mineral origin of asbestos suggests the presence of iron ions that can catalyze reactions that generate oxygen and nitrogen radical residues (ROS and RNS). Second, alveolar and peritoneal macrophages can phagocytose these inflammatory filaments, which induces inflammation with ROS/RNS and cytokine (TNFα, IL-6) production (13). Together, this accumulation of reactive chemical entities (O.
) act as second messengers to induce cellular pathways responsible for uncontrolled proliferation, such as the MAPK, PI3K/Akt, and NF-kB cascades, and DNA damage ( 14 ). It should be noted that ROS and RNS together with asbestos fibers can cause mutagenicity and genotoxicity in mitochondrial cells through physical association with the mitotic system and through direct DNA and chromosomal damage (13). Despite the protective role of manganese superoxide dismutase (Mn SOD) and catalase (CAT) antioxidant systems, asbestos-induced reactive species cause multiple DNA damages, such as DNA single-strand breaks (SSBs), chromosomal fragments, and 8-hydroxydeoxyguanosine ( 8 ). 8-OHdG); this latter is the main product of oxidative damage causing G → T and A → C transversions. These genomic changes are associated with spontaneous oncogene expression and malignant evolution of cells (12). In addition, asbestos fibers can disrupt mitosis due to their ability to puncture the mitotic spindle. This leads to mutations, chromosomal abnormalities and mesothelial cell aneuploidy (7). Several DNA repair mechanisms attempt to repair these genomic breaks, but if the repair enzymes are deficient, they can create another pathway that promotes tumorigenesis and can act synergistically with other pathogenic processes (15). In addition, such fibers are able to bind cellular proteins, preventing them from performing their specific roles, thus impairing the function of mesothelial cells (7). Both cells and macrophages exposed to asbestos can release large amounts of inflammatory cytokines and tumor growth factor β and vascular endothelial growth factor (VEGF), creating a milieu that promotes tumor growth (7). As previously mentioned, these tumor growth factors can activate the PI3K/Akt pathway, which has been shown to play an important role in tumor development and evolution (10). More specifically, the anti-apoptotic activity can be attributed to the main downstream of Akt: mTOR (16). In three-dimensional cultures and ex vivo, mTOR has been identified as a key regulator responsible for the apoptotic resistance of mesothelial cells by activating oncogenic genes such as S6K (17). Interestingly, miRNAs can act as tumor suppressors or oncogenes by targeting specific pathways involved in carcinogenesis. A recent study assessed the expression of miRNAs in MPM and identified their upregulation to inhibit several cascades (such as PIK3-Akt) that could potentially be used to discover new pharmacological targets (18). Alveolar macrophages can also secrete pro-inflammatory cytokines, TNFα, which are involved in cell apoptosis and synovial compensatory proliferation.
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