NK‐ and T‐cell subsets in malignant mesothelioma patients: Baseline pattern and changes in the context of anti‐CTLA‐4 therapy

• Published in: International journal of cancer 2019-10, Vol.145 (8), p.2238-2248
• Main Authors: Sottile, Rosa, Tannazi, Milad, Johansson, Maria H., Cristiani, Costanza Maria, Calabró, Luana, Ventura, Valeria, Cutaia, Ornella, Chiarucci, Carla, Covre, Alessia, Garofalo, Cinzia, Pontén, Victor, Tallerico, Rossana, Frumento, Paolo, Micke, Patrick, Maio, Michele, Kärre, Klas, Carbone, Ennio
• Format: Article
• Language: English
• Subjects: anti-CTLA-4 therapy; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Agents - therapeutic use; Cancer; CD56 Antigen - immunology; CD56 Antigen - metabolism; CD8 antigen; Cell Line, Tumor; Cells, Cultured; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 Antigen - immunology; Cytokines - blood; Cytokines - immunology; Female; Gene Expression Regulation, Neoplastic; Genomes; Humans; Immune checkpoint; immunoprofiling; K562 Cells; Kaplan-Meier Estimate; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lymphocytes; Lymphocytes T; Lysis; Male; malignant mesothelioma; Medical prognosis; Medical research; Medicin och hälsovetenskap; Mesothelioma; Mesothelioma - drug therapy; Mesothelioma - genetics; Mesothelioma - immunology; Mesothelioma, Malignant; Middle Aged; Natural killer cells; NK cells; Pathology; Patologi; Phenotypes; Prognosis; Ribonucleic acid; RNA; Solid tumors; T cells; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Tumor necrosis factor; Tumors
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.32363

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. What's new? Treatment options for malignant mesothelioma (MM) have not significantly improved over the past four decades. A better understanding of the immune response in MM might guide new treatment strategies. In this study, the authors found evidence that natural killer (NK) cells can infiltrate, recognize, and kill MM cells. However, MM patients have distinct alterations in NK, CD8+ T‐cell, and cytokine profiles. Some of these alterations correlated with prognosis, or were affected by treatment with tremelimumab.