• Marc de Perrot, Licun Wu, Michael Cabanero, J Yannis Perentes, Trevor D McKee, Laura Donahoe, Penelope Bradbury, Mikihiro Kohno, Mei-Lin Chan, Junichi Murakami, Shaf Keshavjee, Ming-Sound Tsao, and Cho B C John BCJ Department of Radiation Oncology, University Health Network, University of Toronto, Toronto, Ontario, Canada..
• Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada; Latner Thoracic Surgery Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada. Electronic address: marc.deperrot@uhn.ca.
• J. Thorac. Cardiovasc. Surg. 2020 May 1; 159 (5): 2082-2091.e1.

ObjectiveCytotoxic CD8+ tumor infiltrating lymphocytes (TILs) can contribute to the benefit of hypofractionated radiation, but programmed cell death pathways (programmed cell death 1 and programmed cell death ligand 1 [PD-1/PD-L1]) may provide a mechanism of tumor immune escape. We therefore reviewed the influence of PD-1/PD-L1 and CD8+ TILs on survival after accelerated hypofractionated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma (MPM).MethodsSixty-nine consecutive patients undergoing the protocol of Surgery for Mesothelioma after Radiation Therapy (SMART) between November 2008 and February 2016 were analyzed for the presence of PD-L1 on tumor cells, PD-1 on inflammatory cells, and CD8+ TILs. Comparison was made with a cohort of patients undergoing extrapleural pneumonectomy after induction chemotherapy (n = 14) and no induction (n = 2) between March 2005 and October 2008. PD-L1 expression on tumor cells ≥1% was considered positive. CD8+ TILs and PD-1 expression were scored as a percentage of positive cells.ResultsPD-L1 was negative in 75% of MPM after completion of SMART. CD8+ TILs ranged between 0.24% and 8.47% (median 2%). CD8+ TILs ≥2% was associated with significantly better survival in epithelioid MPM (median survival 3.7 years vs 2.3 years in CD8+ TILs <2%; P = .02). PD-L1 positivity was associated with worse survival in biphasic MPM (median survival, 0.4 years vs 1.5 years in biphasic PD-L1 negative tumors; P = .07) after SMART. Multivariate analysis demonstrated that epithelioid MPM, nodal disease, and CD8+ TILs were independent predictors of survival after SMART.ConclusionsThe influence of tumor microenvironment on survival differs between epithelioid and nonepithelioid MPM. CD8+ TILs is an independent factor associated with better survival in epithelioid MPM treated with SMART.Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

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