Masaki Anraku1, Kristopher S. Cunningham2, Zhihong Yun1, Ming-Sound Tsao2, Li Zhang3, Shaf Keshavjee1, Michael R. Johnston1, Marc de Perrot1; 1Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; 2Division of Applied Molecular Oncology, Ontario Cancer Institute, Toronto, ON, Canada; 3Division of Cellular and Molecular Biology, Toronto General Research Institute, Toronto, ON, Canada
Objective: The role of tumor-infiltrating lymphocytes (TILs) in patients with malignant pleural mesothelioma (MPM) is unknown. The aim of the study was to determine the impact of various subtypes of TILs on survival in MPM.Methods: We performed immunohistochemical analysis of 32 surgical specimens from patients with MPM treated with induction chemotherapy followed by extrapleural pneumonectomy to assess the distribution of TILs. The presence of T-cell subtypes (CD3+, CD4+, and CD8+), regulatory subtypes (CD25+ and FOXP3+), and memory subtype (CD45RO+) were examined. The interrelationship between subpopulations of TILs and survival was investigated.
Results: The median age was 59 years (range, 21-74). The majority of patients presented with stage III (72%) and epithelioid cell type (75%). Induction chemotherapy consisted of cisplatin and vinorelbine (50%), cisplatin and pemetrexed (28%), or others (22%). The median survival was 12.2 months, and the overall 3-year survival was 34.6%. Patients with high levels of CD8+ TILs demonstrated better survival than those with low levels (3 yr-survival: 83.3% versus 27.7%; p=0.059). Moreover, high levels of CD8+ TILs correlated with delayed recurrence (p=0.049). On the contrary, patients with high levels of CD4+ or CD25+ TILs demonstrated shorter survival than those with low levels (3 year-survival: 14.9% versus 53.3%; p=0.082, and 16.8% versus 45.4%; p=0.091, respectively). Interestingly, higher levels of CD8+ TILs were observed in patients treated with cisplatin and pemetrexed than in those treated with cisplatin and vinorelbine (p=0.051). The presence of FOXP3+ TILs did not affect the overall survival or disease-free survival in the study population. In multivariate analysis including age (<60 versus ?60 years), tumor stage (stage II versus stage III, IV), cell type (epithelioid versus others), completeness of resection (R0 versus R1/2), type of induction chemotherapy (cisplatin and pemetrexed versus others), adjuvant hemithoracic radiation (yes versus no) and CD8+ TILs (high versus low levels), high levels of CD8+ TILs remained an independent prognostic factor associated with delayed recurrence (hazard ratio=0.37; 95% confidence interval=0.083-0.91; p=0.028) and better survival (hazard ratio=0.35; 95% confidence interval=0.079-0.85; p=0.017).
Conclusion: We conclude that the presence of CD8+ TILs is associated with better prognosis in MPM. The stimulation of CD8+ lymphocytes can be a potential therapeutic strategy to improve outcome in patients with MPM.
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