G Pasello1, G Zago1, F Lunardi2, L Urso3, I Kern4, G Vlacic4, F Grosso5, M Mencoboni6, G L Ceresoli7, M Schiavon2, F Pezzuto2, A Pavan8, S E Vuljan2, P Del Bianco9, P Conte8, F Rea2, F Calabrese10. 1. Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova. 2. Departments of Cardiac, Thoracic and Vascular Sciences. 3. Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. 4. Pathology Laboratory, University Clinic Golnik, Golnik, Slovenia. 5. Mesothelioma Unit, Oncology, SS Antonio e Biagio General Hospital, Alessandria. 6. Oncology Unit, Villa Scassi Hospital, ASL 3 Genovese, Genova. 7. Oncology, Cliniche Humanitas Gavazzeni, Bergamo. 8. Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova; Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. 9. Clinical Trials and Biostatistics Unit, Istituto Oncologico Veneto IRCCS, Padova, Italy. 10. Departments of Cardiac, Thoracic and Vascular Sciences. Electronic address: fiorella.calabrese@unipd.it.
Abstract
Background: 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. This study retrospectively investigated TME and programmed death ligand 1 (PD-L1) expression in naïve MPM cases and their change under chemotherapy. Patients and methods: Diagnostic biopsies of MPM patients were collected from four Italian and one Slovenian cancer centers. Pathological assessment of necrosis, inflammation, grading, and mitosis was carried out. Ki-67, PD-L1 expression, and tumor infiltrating lymphocytes were detected by immunohistochemistry. When available, the same paired sample after chemotherapy was analyzed. Pathological features and clinical characteristics were correlated to overall survival. Results: TME and PD-L1 expression were assessed in 93 and 65 chemonaive MPM samples, respectively. Twenty-eight samples have not sufficient tumor tissue for PD-L1 expression. 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. Higher CD8+ T lymphocytes, CD68+ macrophages, and PD-L1 expression were associated with pathological features of aggressiveness (necrosis, grading, Ki-67). MPM cases characterized by higher CD8+ T-infiltrate showed lower response to chemotherapy and worse survival at univariate analysis. 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). 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. Conclusions: 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. The role of chemotherapy as a tumor immunogenicity inducer should be confirmed in a larger validation set.
Background: 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. This study retrospectively investigated TME and programmed death ligand 1 (PD-L1) expression in naïve MPM cases and their change under chemotherapy. Patients and methods: Diagnostic biopsies of MPM patients were collected from four Italian and one Slovenian cancer centers. Pathological assessment of necrosis, inflammation, grading, and mitosis was carried out. Ki-67, PD-L1 expression, and tumor infiltrating lymphocytes were detected by immunohistochemistry. When available, the same paired sample after chemotherapy was analyzed. Pathological features and clinical characteristics were correlated to overall survival. Results: TME and PD-L1 expression were assessed in 93 and 65 chemonaive MPM samples, respectively. Twenty-eight samples have not sufficient tumor tissue for PD-L1 expression. 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. Higher CD8+ T lymphocytes, CD68+ macrophages, and PD-L1 expression were associated with pathological features of aggressiveness (necrosis, grading, Ki-67). MPM cases characterized by higher CD8+ T-infiltrate showed lower response to chemotherapy and worse survival at univariate analysis. 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). 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. Conclusions: 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. The role of chemotherapy as a tumor immunogenicity inducer should be confirmed in a larger validation set.
Authors: Nicola Principe; Joel Kidman; Richard A Lake; Willem Joost Lesterhuis; Anna K Nowak; Alison M McDonnell; Jonathan Chee Journal: Front Oncol Date: 2021-04-27 Impact factor: 6.244
Authors: Edwin R Parra; Jie Zhai; Auriole Tamegnon; Nicolas Zhou; Renganayaki Krishna Pandurengan; Carmelia Barreto; Mei Jiang; David C Rice; Caitlin Creasy; Ara A Vaporciyan; Wayne L Hofstetter; Anne S Tsao; Ignacio I Wistuba; Boris Sepesi; Cara Haymaker Journal: Sci Rep Date: 2021-02-25 Impact factor: 4.379