Asbestos exposure is associated with asbestos-related diseases such as asbestosis, pleural plaques, and malignant mesothelioma (MM), a rare and aggressive cancer of the serous membranes. Although the exact mechanism underlying asbestos-related diseases is not yet fully understood, it is suspected that the immune system plays an important role. Immune checkpoints regulate immune responses and are crucial for maintaining immune tolerance, while defects in these mechanisms may lead to the development of cancer. Among the most studied immune checkpoints are programmed cell death receptor 1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), whose genetic polymorphisms may influence the regulation of the immune response. In our study, we investigated the association of polymorphisms in the immune checkpoint genes PD-1 (PDCD1), PD-L1 (CD274), and CTLA-4 (CTLA4) with the risk of asbestos-related diseases and the response to MM treatment with chemotherapy. We conducted two retrospective studies. For the asbestos-related disease risk study, cases included individuals with asbestosis or pleural plaques and MM patients, while controls were asbestos-exposed subjects who did not develop asbestos-related diseases. For the longitudinal study of the response to MM treatment, we included MM patients treated with cisplatin-based chemotherapy. Using bioinformatic analysis, we selected three polymorphisms in the PDCD1 gene (rs2227982, rs222798, rs10204525), three in the CD274 gene (rs2297136, rs4143815, rs4742098) and three in the CTLA4 gene (rs5742909, rs4553808, rs231775) which could influence function of immune checkpoints. Genotyping of selected polymorphisms was performed by competitive allele-specific PCR. Statistical analysis was performed with logistic and Cox regression methods. Our study showed that the CTLA4 rs4553808 polymorphism was associated with the risk of asbestos-related diseases. Carriers of the rs4553808 G allele had a lower risk of developing pleural plaques and MM compared to the control group. In addition, carriers of CTLA4 rs231775 G allele had a higher risk of developing MM than the group of subjects with pleural plaques. Other polymorphisms studied were not associated with any of the asbestos-related diseases. Another important finding of our study is that the CD274 rs2297136 polymorphism is associated with the survival of MM patients treated with chemotherapy. Carriers of the rs2297136 A allele had shorter progression-free survival and shorter overall survival than patients with the normal genotype. Carriers of CTLA4 rs5742909 T were more likely to have a better response to chemotherapy. The results of our study could contribute to a better understanding of the onset and course of diseases associated with asbestos exposure. Genotyping of CD274 and CTLA4 genetic polymorphisms could contribute to the personalized treatment of MM, both with classical cisplatin-based chemotherapy and with immune checkpoint inhibitors.
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