Iris C Salaroglio1, Joanna Kopecka1, Francesca Napoli2, Monica Pradotto3, Francesca Maletta4, Lorena Costardi5, Matteo Gagliasso6, Vladan Milosevic1, Preeta Ananthanarayanan1, Paolo Bironzo7, Fabrizio Tabbò7, Carlotta F Cartia6, Erika Passone5, Valentina Comunanza8, Francesco Ardissone6, Enrico Ruffini5, Federico Bussolino8, Luisella Righi9, Silvia Novello7, Massimo Di Maio10, Mauro Papotti4, Giorgio V Scagliotti7, Chiara Riganti11. 1. Department of Oncology, University of Torino, Torino, Italy. 2. Pathology Unit, Department of Oncology at San Luigi Hospital, University of Torino, Orbassano, Italy. 3. Thoracic Oncology Unit and Medical Oncology Division, Department of Oncology at San Luigi Hospital, University of Torino Regione Gonzole 10, Orbassano, Italy. 4. Department of Oncology, University of Torino, Torino, Italy; Pathology Unit, Department of Oncology at AOU Città della Salute e della Scienza, Torino, Italy. 5. Thoracic Surgery Unit, Department of Surgery, AOU Città della Salute e Della Scienza, University of Torino, Torino, Italy. 6. Thoracic Surgery Unit, Department of Oncology at San Luigi Hospital, University of Torino, Orbassano, Italy. 7. Department of Oncology, University of Torino, Torino, Italy; Thoracic Oncology Unit and Medical Oncology Division, Department of Oncology at San Luigi Hospital, University of Torino Regione Gonzole 10, Orbassano, Italy. 8. Department of Oncology, University of Torino, Torino, Italy; Candiolo Cancer Institute - FPO IRCCS, Candiolo, Department of Oncology, University of Torino, Candiolo, Italy. 9. Department of Oncology, University of Torino, Torino, Italy; Pathology Unit, Department of Oncology at San Luigi Hospital, University of Torino, Orbassano, Italy. 10. Department of Oncology, University of Torino, Torino, Italy; Medical Oncology Division, Department of Oncology at AOU Ordine Mauriziano di Torino, Torino, Italy. 11. Department of Oncology, University of Torino, Torino, Italy; Interdepartmental Center "G. Scansetti" for the Study of Asbestos and Other Toxic Particulates, University of Torino, Torino, Italy. Electronic address: chiara.riganti@unito.it.
Abstract
INTRODUCTION: A comprehensive analysis of the immune cell infiltrate collected from pleural fluid and from biopsy specimens of malignant pleural mesothelioma (MPM) may contribute to understanding the immune-evasion mechanisms related to tumor progression, aiding in differential diagnosis and potential prognostic stratification. Until now such approach has not routinely been verified. METHODS: We enrolled 275 patients with an initial clinical diagnosis of pleural effusion. Specimens of pleural fluids and pleural biopsy samples used for the pathologic diagnosis and the immune phenotype analyses were blindly investigated by multiparametric flow cytometry. The results were analyzed using the Kruskal-Wallis test. The Kaplan-Meier and log-rank tests were used to correlate immune phenotype data with patients' outcome. RESULTS: The cutoffs of intratumor T-regulatory (>1.1%) cells, M2-macrophages (>36%), granulocytic and monocytic myeloid-derived suppressor cells (MDSC; >5.1% and 4.2%, respectively), CD4 molecule-positive (CD4+) programmed death 1-positive (PD-1+) (>5.2%) and CD8+PD-1+ (6.4%) cells, CD4+ lymphocyte activating 3-positive (LAG-3+) (>2.8% ) and CD8+LAG-3+ (>2.8%) cells, CD4+ T cell immunoglobulin and mucin domain 3-positive (TIM-3+) (>2.5%), and CD8+TIM-3+ (>2.6%) cells discriminated MPM from pleuritis with 100% sensitivity and 89% specificity. The presence of intratumor MDSC contributed to the anergy of tumor-infiltrating lymphocytes. The immune phenotype of pleural fluid cells had no prognostic significance. By contrast, the intratumor T-regulatory and MDSC levels significantly correlated with progression-free and overall survival, the PD-1+/LAG-3+/TIM-3+ CD4+ tumor-infiltrating lymphocytes correlated with overall survival. CONCLUSIONS: A clear immune signature of pleural fluids and tissues of MPM patients may contribute to better predict patients' outcome.
INTRODUCTION: A comprehensive analysis of the immune cell infiltrate collected from pleural fluid and from biopsy specimens of malignant pleural mesothelioma (MPM) may contribute to understanding the immune-evasion mechanisms related to tumor progression, aiding in differential diagnosis and potential prognostic stratification. Until now such approach has not routinely been verified. METHODS: We enrolled 275 patients with an initial clinical diagnosis of pleural effusion. Specimens of pleural fluids and pleural biopsy samples used for the pathologic diagnosis and the immune phenotype analyses were blindly investigated by multiparametric flow cytometry. The results were analyzed using the Kruskal-Wallis test. The Kaplan-Meier and log-rank tests were used to correlate immune phenotype data with patients' outcome. RESULTS: The cutoffs of intratumor T-regulatory (>1.1%) cells, M2-macrophages (>36%), granulocytic and monocytic myeloid-derived suppressor cells (MDSC; >5.1% and 4.2%, respectively), CD4 molecule-positive (CD4+) programmed death 1-positive (PD-1+) (>5.2%) and CD8+PD-1+ (6.4%) cells, CD4+ lymphocyte activating 3-positive (LAG-3+) (>2.8% ) and CD8+LAG-3+ (>2.8%) cells, CD4+ T cell immunoglobulin and mucin domain 3-positive (TIM-3+) (>2.5%), and CD8+TIM-3+ (>2.6%) cells discriminated MPM from pleuritis with 100% sensitivity and 89% specificity. The presence of intratumor MDSC contributed to the anergy of tumor-infiltrating lymphocytes. The immune phenotype of pleural fluid cells had no prognostic significance. By contrast, the intratumor T-regulatory and MDSC levels significantly correlated with progression-free and overall survival, the PD-1+/LAG-3+/TIM-3+ CD4+ tumor-infiltrating lymphocytes correlated with overall survival. CONCLUSIONS: A clear immune signature of pleural fluids and tissues of MPM patients may contribute to better predict patients' outcome.
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