Prognostic influence of tumor microenvironment after hypofractionated radiation and surgery for mesothelioma

Objective: Cytotoxic 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). Methods: Sixty-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. Results: PD-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. Conclusions: The 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.