![]() ![]() Non-genetic determinants of heterogeneity have also garnered significant interest, as even genetically identical cells may harbor unique chemosensitivity profiles. Moreover, genetic heterogeneity has also been identified across patients, and the incidence of clinically actionable mutations differs significantly between tumors arising from different tissue or cell types, amongst patients with the same class of tumor, and between matched primary and metastatic tumors within the same patient. Thus, next generation sequencing of multiple tumor types identifying the association between increased clonal heterogeneity and higher pathological stage and/or worse prognosis. Genomics has provided the most extensive insights to date about tumor-intrinsic variations, with sequencing studies revealing a large extent of clinically-relevant intra-tumor heterogeneity. Within individual tumors, significant differences in the molecular and phenotypic profiles may arise from tumor cell-intrinsic or extrinsic factors. The role of chemotherapy as a tumor immunogenicity inducer should be confirmed in a larger validation set.Recent advances in our understanding of cancer, driven by the development of sophisticated biochemical and molecular techniques, have highlighted the complex and heterogenous nature of this disease. TME enriched with cytotoxic T lymphocytes is associated with higher levels of macrophages and PD-L1 expression on tumor cells and with aggressive histopathological features, lower response to chemotherapy and shorter survival. Subgroup exploratory analysis of 15 paired samples before and after chemotherapy showed a significant increase in cytotoxic T lymphocytes in MPM samples and PD-L1 expression in immune cells. Patients stratification according to a combined score including CD8+ T lymphocytes, necrosis, mitosis, and proliferation index showed median overall survival of 11.3 months compared with 16.4 months in cases with high versus low combined score (P < 0.003). MPM cases characterized by higher CD8+ T-infiltrate showed lower response to chemotherapy and worse survival at univariate analysis. Higher CD8+ T lymphocytes, CD68+ macrophages, and PD-L1 expression were associated with pathological features of aggressiveness (necrosis, grading, Ki-67). Sarcomatoid/biphasic samples were characterized by higher CD8+ T lymphocytes and PD-L1 expression on tumor cells, while epithelioid showed higher peritumoral CD4+ T and CD20+ B lymphocytes. Twenty-eight samples have not sufficient tumor tissue for PD-L1 expression. TME and PD-L1 expression were assessed in 93 and 65 chemonaive MPM samples, respectively. Pathological features and clinical characteristics were correlated to overall survival. When available, the same paired sample after chemotherapy was analyzed. Ki-67, PD-L1 expression, and tumor infiltrating lymphocytes were detected by immunohistochemistry. Pathological assessment of necrosis, inflammation, grading, and mitosis was carried out. This study retrospectively investigated TME and programmed death ligand 1 (PD-L1) expression in naïve MPM cases and their change under chemotherapy.ĭiagnostic biopsies of MPM patients were collected from four Italian and one Slovenian cancer centers. Tumor immune microenvironment (TME) plays a key role in malignant pleural mesothelioma (MPM) pathogenesis and treatment outcome, supporting a role of immune checkpoint inhibitors as anticancer approach. ![]()
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