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 evasion. Yet, cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) can contribute to the benefit of hypofractionated radiation. For malignant pleural mesothelioma, researchers determined the impact of PD-1/PD-L1 and CD8+ TILs on survival after accelerated hypofractionated hemithoracic radiotherapy followed by extrapleural pneumonectomy (MPM). Between November 2008 and February 2016, 69 patients who underwent the Surgery for Mesothelioma After Radiation Therapy (SMART) protocol were examined for the presence of PD-L1 on tumor cells, PD-1 on inflammatory cells, and CD8+ TILs. Between March 2005 and October 2008, a cohort of patients undergoing extrapleural pneumonectomy after induction chemotherapy (n=14) and without induction (n=2) was compared. PD-L1 expression of less than 1% on tumor cells was considered positive. They calculated the percentage of positive cells for CD8+ TILs and PD-1 term.

After SMART, PD-L1 was negative in 75% of MPM. CD8+TILs cells varied from 0.24% to 8.47% (median 2%). In epithelioid MPM, CD8+ TILs ≥ 2% were linked with significantly improved survival (median survival 3.7 years vs. 2.3 years in CD8+ TILs < 2%; P=.02). After SMART, biphasic MPM with PD-L1 positivity had a worse survival rate (median survival, 0.4 years versus 1.5 years in biphasic PD-L1 negative tumors; P =.07). Epithelioid MPM, nodal disease, and CD8+ TILs were all independent predictors of survival after SMART in multivariate analysis. The impact of the tumor microenvironment on survival varies depending on whether the MPM is epithelioid or nonepithelioid. In epithelioid MPM treated with SMART, CD8+ TILs are an independent factor linked with higher survival.