**7. Conclusion**

Thus, our studies clarified a number of characteristics pertaining to asbestosinduced immunological impairment in acquired immunity as well as in innate immunity, some of which were also actually observed in patients with malignant mesothelioma. **Figure 1** summarizes those immune-suppressive effects of asbestos which presumably contribute to the development of malignant mesothelioma. Asbestos exposure suppressed immune-activating functions (Th1) and natural (NK) and acquired cytotoxicity (CTLs), whereas asbestos augmented functions of suppressive T lymphocytes (Tregs). Additionally, high production of TGF-β by long-surviving macrophages (Mϕ) caused by asbestos contributes to lung fibrosis as well as immune suppression. The immunological conditions generated by those characteristics allow abnormal cells caused by cellular toxicity of asbestos to escape from immune surveillance and survive to develop malignant mesothelioma. As mentioned above, it is actual that some of the characteristics caused by asbestos exposure were also shown in patients with malignant mesothelioma. Interestingly, plaque-positive subjects (without tumors) showed no impairment in some functions compared with mesothelioma patients, suggesting that their sustained immune functions protected them from malignant mesothelioma following asbestos exposure. On the basis of our present knowledge, we recently undertook a comprehensive analysis of the immunological characteristics of peripheral blood of mesothelioma patients as well as plaque-positive subjects. Parameters examined included cell surface markers, mRNA expression, and plasma cytokine concentrations. From the results of these analyses, we established three formulae for scoring mesothelioma, pleural plaque without tumors, and asbestos exposure (for both mesothelioma patients and plaque-positive subjects) (international patent

#### **Figure 1.**

*Summarized illustration of the findings concerning a suppressed immune system caused by exposure to asbestos obtained from our studies. It was found that asbestos exposure showed immunological effects on various kinds of cells (purple arrows). Asbestos exposure during culture caused decreases in natural and acquired cytotoxicity and Th1 function associated with decreases in expression of NKp46, perforin, IFN-γ, TNF-α, and CXCR3 (colored red). In contrast, asbestos exposure caused increases in Treg function as well as fibrogenic/suppressive macrophages associated with increases in expression of CTLA-4, TGF-β, and IL-10 (colored blue). Those suppressed immune functions presumably allow abnormal mesothelial cells, arising from healthy cells caused by toxicity of asbestos, to escape from immune surveillance and survive to develop into malignant mesothelioma.*

*Suppressed Immune System Caused by Exposure to Asbestos and Malignant Mesothelioma DOI: http://dx.doi.org/10.5772/intechopen.90763*

pending). The immunological screening devices might contribute to the detection of subgroups of people who have suppressed immune functions among people exposed to asbestos prior to diagnosis by CT images and histological observations. Moreover, those of our knowledge encourage us to treat mesothelioma with some kinds of immunotherapy. It is reasonable to assume that inhibitors targeting on Treg cells or suppressive macrophages might contribute to treatment of malignant mesothelioma. In addition, it has also been found that asbestos-caused decrease in cytotoxicity of CTL was improved by exogenous IL-2, but not accompanied with restoration of cell surface markers [72], which suggests that an appropriate immunotherapy might be developed to augment antitumor immunity in patients with mesothelioma as well as subjects exposed to asbestos. Thus, our studies could further our understanding of the immunological mechanisms associated with asbestos-induced malignant mesothelioma and perhaps facilitate the development of methodologies that can be employed for the early detection as well as treatment of mesothelioma. These are issues we intend to further address in the future.

### **Acknowledgements**

The authors thank Ms. Tamayo Hatayama, Shoko Yamamoto, Miho Ikeda, and Ayasa Kamezaki for their technical assistance. Grant support from JPSS KAKENHI Grants (17790375, 18790386, 18390186, 19790411, 19790431, 20890270, 20390178, 22700933, 22790550, 23790679, 24590770, 25860470, 16 K09114, 16H05264, and 19H03892) and Kawasaki Medical School Project Grant (17-210S, 17-404 M, 18-209 T, 18-403, 19-205Y, 19-407 M, 20-210O, 20-411I, 21-107, 21-201, 21-401, 22-A29, 23B66, 23P3, and 28B051) is gratefully acknowledged.

### **Conflict of interest**

The authors declare that there is no conflict of interest regarding the publication of this paper.

#### **Author details**

Yasumitsu Nishimura\*, Naoko Kumagai-Takei, Suni Lee, Kei Yoshitome and Takemi Otsuki Department of Hygiene, Kawasaki Medical School, Kurashiki, Japan

\*Address all correspondence to: yas@med.kawasaki-m.ac.jp

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
