Tumor Microenvironment of Malignant Pleural Mesothelioma

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1		Mark Jaradeh	--	2602	2022-09-13 20:57:00	\|
2	format change	Peter Tang	Meta information modification	2602	2022-09-14 04:37:03	\|

This entry is adapted from the peer-reviewed paper 10.3390/cancers14184415

Malignant pleural mesothelioma is a rare disease with an annual incidence of around 3000 cases a year in the United States. Most cases are caused by asbestos exposure, with a latency period of up to 40 years. Pleural mesothelioma is an aggressive disease process with overall survival of roughly 6–12 months after the time of diagnosis. It is divided into three subtypes: epithelioid, mixed type, and sarcomatoid type, with the epithelioid subtype having the best overall survival. Often, the treatment is multimodality with surgery, chemotherapy, and radiation. The survival benefit is improved but remains marginal. New treatment options involving targeted immune therapies appear to offer some promise. The tumor microenvironment is the ecosystem within the tumor that interacts and influences the host immune system.

mesothelioma pleura immune microenvironment

1. Introduction

Malignant pleural mesothelioma (MPM) is a rare disease process that arises from mesothelial membranes and often affects the pleura and peritoneum. The pathophysiology of the disease process is intimately linked to asbestos exposure, with a latent period of about 40 years prior to presentation. When it involves the pleura, which is the commonest type, patients present with dyspnea, chest pain, fatigue, or weight loss. On imaging, there is often a pleural effusion with associated pleural thickening or a pleural-based mass. It is a highly aggressive tumor, and even with current treatment regimens, the overall median survival is around 17 months, and the 5-year overall survival is about 10%. Due to the regulated use of asbestos in the United States, the incidence of MPM is decreasing; however, in other countries such as China, Russia, and Western Europe, the incidence of MPM is on the rise ^[1].

Patients who are deemed resectable are typically treated with trimodality therapy with chemotherapy, surgery, and radiation therapy. Unfortunately, most patients present with advanced-stage disease and are unable to be offered surgery and are treated with first-line therapy with cisplatin/pemetrexed chemotherapy. Despite advances in surgical technique, chemotherapy, and delivery of radiation, the mean survival benefit for resectable disease remains marginal ^[2]^[3].

One area of interest that has revolutionized cancer therapy has been the discovery of immune checkpoint inhibitors. For example, the use of nivolumab and ipilimumab in other types of cancers such as melanoma, non-small-cell lung cancer, and renal cell carcinoma have shown promise in enhancing the antitumor function of T-cell responses and, when used in combination with traditional chemotherapy regimens, have shown a survival benefit ^[4]^[5].

2. Epidemiology

MPM is a rare tumor with an annual incidence of 3000 cases per year in the United States. More than 80% of mesothelioma cases are due to asbestos exposure, with a latency period of up to 40 years after exposure. Other risk factors include Simian Virus 40 (SV40) infection, prior chest wall radiation, and genetic factors such as a mutated BRCA1 associated protein 1 (BAP1) gene. MPM is more common in males, and despite increased regulation on asbestos, rates have not decreased over the past 30 years. This is likely due to prior exposure in the 1970s and the latency period of the disease process that manifests in the decades after exposure. Currently, due to government regulatory efforts asbestos exposure and industrial use have substantially declined in the US. In contrast, worldwide, due to the lack of regulations, industrial mining of asbestos, and continued exposure, epidemiologic studies suggest that the incidence of MPM is continuing to increase ^[1]^[6]^[7]^[8].

MPM is an extremely aggressive tumor that originates in the serosal surfaces of the pleura, peritoneum, pericardium, and tunica vaginalis where mesothelial membranes are. It is classified histologically into three subtypes: epithelioid, biphasic/mixed type, and sarcomatoid type. The epithelial subtype is the most common subtype, representing approximately 50% of cases, and is associated with the best overall prognosis. The sarcomatoid subtype makes up about a quarter of cases and is associated with poor prognosis. A recent population study from the national cancer database of over 19,000 patients with MPM demonstrated that patients with sarcomatoid histology have locally advanced disease at the time of presentation. On multivariable analysis, sarcomatoid and its desmoplastic subvariant and biphasic/mixed subtype histology were independent predictors of worse survival. Notably, desmoplastic malignant mesothelioma, a subvariant of sarcomatoid type, is characterized histologically by dense stromal fibrosis and has the worst prognosis overall. Other clinical variables that are associated with poor prognosis include poor performance status (inability to perform 6 min walk test, ECOG score 3 or more), age 75 or more, government insurance, median income less than USD 63,000, tumor stage, tumor volume, and elevated LDH ^[6]^[7].

3. Pathophysiology

The pathophysiology of MPM is extremely complex with multiple cellular and environmental interactions, all of which appear to be linked to a chronic inflammatory state, ultimately leading to malignant mesothelial cell transformation, proliferation, and a unique tumor microenvironment. Most cases of MPM are due to occupational exposure to asbestos, followed by an intense immune response leading to malignant proliferation. Typically, it is seen in workers who have had many years of high-level occupational exposure. Studies have shown an exposure dose threshold of 25 to 100 fibers/mL/yr significantly increases the risk of developing MPM, and the latency period is inversely proportional to exposure level. Asbestos is a unique crystalline molecule that lends itself to inducing a robust and protracted immune response with excessive cellular proliferation and collagen deposition. The geometry and dimensions of each subtype may govern their deposition and clearance kinetics, biological reactivity, and dissolution in the lung. Furthermore, the chemical composition and surface properties, including absorption, oxidation/reduction reactions, and charge, also play a role in biopersistence, cellular responses, and pathogenicity. Importantly, smoking seems to have a synergistic effect on the pathogenesis of MPM. Some evidence suggests that smoke exposure increases the rate of asbestos fiber retention, thus promoting and exacerbating the effects of asbestos. Typically, asbestos fibers will cause a diffuse interstitial fibrosis in the lower lung zones, with worse disease closest to the pleura and honeycombing of the lung in advanced cases. Microscopically, the disease process is defined by diffuse interstitial fibrosis and the presence of asbestos bodies ^[6]^[7].

The initial insult begins when mesothelial cells encounter asbestos fibers and generate multiple macrophage attractants (CCL2, IL-6, IL-8, macrophage inflammatory protein-1, granulocyte colony-stimulating factor, and granulocyte/macrophage colony-stimulating factor), which begins the inflammatory cascade. In vitro and in vivo studies have demonstrated that upon exposure to asbestos, macrophages attempt to phagocytose asbestos fibers but, due to their size, are unable to do so. This phenomenon of the “frustrated macrophage” then triggers a cytokine cascade and formation of reactive oxygen species that promote a persistent proinflammatory state, which eventually leads to DNA damage, gene deletions, and tissue hypoxia. In addition, the alveolar macrophage (AM) response promotes a chronic inflammatory state, induces fibrosis, and upregulates the expression of genes linked to cellular proliferation and collagen deposition ^[6].

Macrophages are also responsible for allowing damaged mesothelial cells that should normally be targeted for apoptosis to evade the immune system. Cells that have sustained genomic insult are ordinarily marked for poly(ADP)ribose polymerase-induced programmed cell death but, under certain signaling influences, are rescued from being terminated by aspects of the inflammatory response. In vitro experiments have shown that increased levels of TNF-α from persistently activated macrophages upregulate the NF-κβ pathway and subvert mesothelioma cells from programmed cell death ^[6].

Finally, a growing body of research into cytogenetics and molecular genetics has explored new insights into the pathogenesis of this malignancy. Recent evidence suggests that the extracellular matrix (ECM) may have implications in the pathogenesis of MPM, in which the surrounding stroma promotes tumor growth, invasion, and protection from the antitumor response. Many genes related to the synthesis of and interaction with the extracellular matrix (ECM) are upregulated in patients with MPM, which help promote a protumor environment. The more aggressive forms of MPM (biphasic/mixed subtype, desmoplastic and sarcomatoid) are associated with upregulation of matrix metalloproteases (MPPs), which promote cellular invasion ^[2]^[5].

4. Tumor Microenvironment: Cellular Makeup and Molecular Signaling

The understanding of the immune system and its interaction with cancer cells has unfolded over the last 20 years, leading to a whole field study and investigation into the intricate relationship between tumors and immune cells. The tumor microenvironment is the complex and fluid interaction of proliferating tumor cells, extracellular matrix, nutrients, cytokines, and immune cells, specifically, tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs), that help promote tumor growth and metastases. Understanding this complex relationship has led to the development of new treatments in multiple solid-organ tumors and may offer potential drug targets in the treatment of MPM. The immune system is instrumental in assessing the host environment for potential threats. Tumor surveillance begins with “immune editing”, which describes the phenomena of an immune competent host developing cancer in the setting of active immunosurveillance. It is divided into three phases: elimination, equilibrium, and escape. During the elimination phase, the host immune system is upregulated, and host mechanisms can induce apoptosis of tumor cells. If this process is unsuccessful and tumor cells are not fully eradicated, then the tumor will enter the equilibrium phase. This phase is defined by tumor growth and maintenance, which eventually will lead to disease progression. In the escape phase, malignant cells will adapt to the host immune environment and go on to further develop tumor variants that can circumvent the cytotoxic capabilities of the host immune system and eventually lead to tumor metastasis ^[7]^[9].

Macrophages are typically one of the first immune cells involved in the initial response to antigens and have a myriad of functions. They are derived from monocytes and after several stages of development within the bone marrow are released into peripheral circulation and migrate into resident tissues and differentiate into macrophages. They have tremendous plasticity and, depending on the tumor microenvironment, can support or combat tumor cells. Local cytokine production and ligands will stimulate macrophages to either M1 or M2 tissue-associated macrophages (TAMs). The Ujiie study found that TAMs (CD163+ macrophages) and their ratio with biologically relevant TILs (CD8 and CD20 lymphocytes) were independent predictors of survival in epithelioid MPM. In patients that had not undergone neoadjuvant chemotherapy, high stromal CD163+ TAMs/M2 tumor-associated macrophages were associated with poor survival. Interestingly, it appears that CD163+ TAMs secrete immunosuppressive cytokines and support tumor progression, invasion, angiogenesis, and metastases. The interaction with MPM cells appeared to shift mature macrophages toward the M2 phenotype, which is characterized by poor antigen presentation and increased immunosuppressive activity. Studies have shown that when macrophages are exposed to MPM cells, they produce higher amounts of prostaglandin E2, an arachidonic acid metabolite, which has been shown to stimulate the development of regulatory T cells (Tregs), which in turn will downregulate the host T-cell response. Furthermore, some evidence suggests that TAMs can upregulate IL-10 and B7-H3 on tumor cells, both of which are known to downregulate the immune response and inhibit antitumor T-cell responses ^[10]^[11].

B lymphocytes (CD20+), a component of the adaptive immune response, are also fundamental in mounting an effective host immune response and have multiple roles in the immune system. TAMs produce stimulatory signals to B lymphocytes, leading to migration into the tumor microenvironment. Once in tissues, they can function as antigen-presenting cells and provide costimulatory signals to T cells, or they can differentiate into antibody-secreting plasma cells.

T cells are part of the adaptive immune response. They originate in the bone marrow and then migrate to the thymus gland and mature into distinct cell lines (CD4+, CD8+, regulatory T cells) with various functions. CD8+ “killer T cells” use T-cell receptors (TCRs) to recognize antigenic peptides bound to MHCI molecules on the surface of cells infected with viruses or mutated cancer cells and induce apoptosis. They also produce tumor necrosis alpha (TNFα) and interferon-gamma (IFNγ). The Ujiie study also showed that although not statistically significant, a high density of CD8 TILs in tumors tended to exhibit an improved overall survival in patients with MPM. Anraku et al. performed an immunohistochemical analysis of 32 patients who had undergone extrapleural pneumonectomy to assess the distribution of helper, cytotoxic killer, and regulatory T cells. Based on their multivariate analysis, they demonstrated that patients who expressed high levels of CD8+ TILs conferred a more favorable overall survival, disease-free progression, and reduced frequency of lymph node metastases than in patients with higher expression of regulatory and CD4+ T cells. ^[11]^[12].

Cancer tissues are diverse and composed of various types of cells with distinct molecular and phenotypic features. Malignant cells are adaptable and due to the changing environment and immune response, they can differentiate into subclones and evolve. Understanding intratumoral heterogeneity and the relationship to the tumor microenvironment is clinically important because it could potentially impact therapies. Kiytoani and colleagues completed multiregional DNA sequencing on six patients from geographically different regions of MPM tumors (anterior, posterior, and diaphragm) and characterized somatic mutations within each region, mutation/neoantigen load, spatial heterogeneity of somatic mutations of cancer cells, and tumor-infiltrating lymphocytes. Their analysis identified distinct patterns of somatic mutations and immune microenvironment signatures (TCRβ repertoires) and immune microenvironment both intratumorally and between each patient. In their study, they identified the active and suppressive sides of the tumor immune microenvironment that can coexist at the same time. They demonstrated that higher cytolytic activity, represented by the PRF1/TRB ratio in tumor sites, correlated with higher numbers of somatic mutation/neoantigen load, and more robust expansion of TILs. However, they also found that the FOXP3/TRB ratio, which represents Treg activity, was also higher within tumor positions with higher mutation/neoantigen load, and that these areas also expressed lower diversity of TILs. This indicates a balance between immune cell activation and inhibition within the tumor microenvironment, and that once CD8+ TILs are activated and try to eradicate tumor cells, immune suppressive molecules and Tregs may respond and inadvertently assist cancer cells in escaping the host immune system ^[13].

Investigations into immune system cytokine pathways have also expanded the knowledge of the communication and signaling pathways. Another component of the tumor immune microenvironment is the mesothelioma secretome and metabolome, both of which promote chemotaxis and cellular differentiation through chemokines, growth factors, and metabolites. The mesothelioma secretome includes the chemokines CCL2, CCL4, CXCL10, CXCL5, CXCL1, and CXCL12, the cytokines IL-10, IL-6, and growth factors TGFB, VEGF, MCSF, GM-CSF, G-CSF, FGF, and PDGF. Hypoxia is one of the cardinal features of the metabolome and can promote tumor evasion from the host immune system and enhance the growth of mesothelioma cell lines. Specifically, hypoxia induces upregulation of PD-L1 expression in tumor cell lines, which in turn downregulates the host immune system. Other examples of upregulation of gene expression in mesothelioma cells include glucose transporter 1 (Glut1) receptors and L-type amino acid transporter 1 (LAT1), both of which provide a competitive advantage for nutrients to tumor cells over the host immune system ^[9].

One cytokine that has been identified as an important immune regulatory agent is interlukin-7 (IL-7). IL-7 is essential for the development and homeostatic maintenance of T and B lymphocytes. Binding to the IL-7 receptor activates multiple pathways that regulate lymphocyte survival, proliferation, and differentiation. Studies have shown that patients with high tumor expression levels of interleukin-7 receptor (IL-7R) are associated with poor prognosis and upregulation of regulatory T cells (T regs). Studies in other cancers have demonstrated that elevated levels of Tregs in tumor beds and peripheral blood samples predict poor survival, and this has also been shown to correlate in patients with MPM. In breast and lung cancer, IL-7 has also been shown to upregulate vascular endothelial growth factor, promoting angiogenesis and tumor growth. It has been postulated that IL-7/IL-7R signaling may promote tumor growth by two separate signaling pathways, angiogenesis and the upregulation of Tregs, thereby decreasing cytotoxic T-cell activity. Therefore, the development of therapeutic targets on the IL-/IL-7R signaling axis may provide an attractive option for drug development ^[14].

References

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