## 3 The Mesotheliomagenic Activity of CNT: A Remaining Issue
### Advances in Understanding Mesothelioma Development
#### 3.2.3 Tolerant Microenvironment and Immunosuppressive Cells within Mesothelial Tumors  
Overall, these convincing data therefore demonstrate that chronic inflammation contributes to the initiation, promotion and progression of MM. However, several recent studies have suggested additional mechanisms to explain the varied pathological profiles among clinical cases. In recent years, a new concept was developed proposing that the immune evasion permits mesothelioma to evade host anti-tumor responses [79; 80; 81]. It is now admitted that hematopoietic and lymphocytic immune cells infiltrating MM are reprogrammed by their new microenvironment and play a critical role in the maintenance and progression of cancer. These immunosuppressive or immunoregulatory cells create a tolerant environment by blocking T lymphocytes (dedicated to recognize and eliminate mutated cells) and stimulate tumor growth by promoting angiogenesis, stroma deposition and metastatic tumor formation [82]. Immunosuppressive host cells invading mesothelioma include regulatory T lymphocytes (T regs) [83; 84], Myeloid-Derived Suppressor Cells (MDSCs) [85] and Tumor-Associated Macrophages (TAMs) [86; 87]. Soluble factors (IL-10, TGF-\(\beta\) and PGE2) and immune checkpoint ligands (PD-1 and CTLA-4) represent the main elements contributing to the establishment of an immunosuppressive microenvironment [79]. The discovery of this tolerant tumor environment resulted in new clinical approaches to control mesothelioma. Immunotherapy aims to boost immunity and block immunosuppressive capacities of tumor cells. The current clinical option to reverse immunosuppressive mechanisms is to inhibit immune checkpoints (anti CTLA-4 and PDL-1 neutralizing antibodies) during cytoreduction therapy (chemotherapy, radiotherapy and surgery) [80; 88; 89; 90]. Tumor immune escapes are also operative in animal models of mesothelioma and innovative therapeutic strategies modifying immunosuppressive monocyte and macrophage differentiation are now successfully obtained [77; 91]. 2.4 The Co-Existence of Early Inflammation and Immunosuppression after Mesotheliomagenic Particle-Exposure  
Our team was able to demonstrate that immunosuppressive responses were not exclusively generate by tumor cells but also by mesothelioma CNT themselves. Indeed, we demonstrated that mesothelioma CNT induce an early immunosuppressive environment by recruiting immunosuppressive M-MDSCs and macrophages after few days in injected rats (Figures 1 and 2) [92]. This effect is associated with the acute neutrophil inflammation already well described (see above). The early presence of MDSC was later confirmed by other teams [93; 94]. Increased expression of immunosuppressive mediators such as IL-10, TGF-\(\beta\), NADPH oxidase and prostaglandin synthase was also noted in murine lungs after acute exposure to mesothelioma CNT [95; 96]. The rapid development of local and systemic immunosuppressive immune responses reduce the number of circulating T lymphocytes and their ability to proliferate [97; 98; 99]. This effect is mainly related to IL-10 and TGF-\(\beta\)[96]. [PERSON] and colleagues also noted a rapid increase of IL-10 expression by macrophages after CNT inhalation in rats [100]. IL-10 release by macrophages results in IL-2 deficiency (an essential factor for T cell proliferation) and reduces antitumor activity of T lymphocytes. Altogether, these results indicate that CNT rapidly induce an immunosuppressive environment, affect T lymphocyte activity and expand transformed mesothelial cells generated by conjoint inflammatory elements (Figure 2). The requirement of these dual environments can explain the diversity of mesothelioma types and long latency period of the disease. Figure 2: A new pathological pathway governs carcinogenesis induced by mesothelioma needed CNT-N. Persistent inflammation and immunosuppression orchestrate carcinogenesis and mesothelioma. Toxic CNT-N induce an inflammatory cascade (in blue) resulting in the influx of inflammatory macrophages and neutrophils.