NK- and T-cell subsets in malignant mesothelioma patients: Baseline pattern and changes in the context of anti-CTLA-4 therapy |
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Authors: | Rosa Sottile Milad Tannazi Maria H. Johansson Costanza Maria Cristiani Luana Calabró Valeria Ventura Ornella Cutaia Carla Chiarucci Alessia Covre Cinzia Garofalo Victor Pontén Rossana Tallerico Paolo Frumento Patrick Micke Michele Maio Klas Kärre Ennio Carbone |
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Affiliation: | 1. Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden;2. Department of Pharmaceutical Science, Faculty of Science, Utrecht University, Utrecht, Netherlands;3. Tumor Immunology and Immunopathology Laboratory, Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy;4. Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy;5. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala University Hospital, Uppsala, Sweden;6. Institute of Environmental Medicine, Unit of Biostatistics, Karolinska Institutet, Stockholm, Sweden |
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Abstract: | Malignant mesothelioma (MM) is a highly aggressive form of cancer with limited treatment options. Although the role of NK cells has been studied in many solid tumors, the pattern of NK-cell subsets and their recognition of mesothelioma cells remain to be explored. We used RNA expression data of MM biopsies derived from the cancer genome atlas to evaluate the immune cell infiltrates. We characterized the phenotype of circulating NK and T cells of 27 MM patients before and after treatment with an anti-CTLA-4 antibody (tremelimumab). These immune cell profiles were compared to healthy controls. The RNA expression data of the MM biopsies indicated the presence of NK cells in a subgroup of patients. We demonstrated that NK cells recognize MM cell lines and that IL-15 stimulation improved NK cell-mediated lysis in vitro. Using multivariate projection models, we found that MM patients had a perturbed ratio of CD56bright and CD56dim NK subsets and increased serum concentrations of the cytokines IL-10, IL-8 and TNF-α. After tremelimumab treatment, the ratio between the CD56bright and CD56dim subsets shifted back towards physiological levels. Furthermore, the improved overall survival was correlated with low TIM-3+CD8+ T-cell frequency, high DNAM-1+CD56dim NK-cell frequency and high expression levels of NKp46 on the CD56dim NK cells before and after immune checkpoint blockade. Together, our observations suggest that NK cells infiltrate MM and that they can recognize and kill mesothelioma cells. The disease is associated with distinct lymphocytes patterns, some of which correlate with prognosis or are affected by treatment with tremelimumab. |
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Keywords: | malignant mesothelioma NK cells T cells immunoprofiling anti-CTLA-4 therapy |
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