Memorial Sloan Kettering Cancer Center, New York, NY
Jarushka Naidoo , Keith Steele , Camelia S. Sima , Jianda Yuan , Paul B. Robbins , Andre L. Moreira , Maria Catherine Pietanza , Jedd D. Wolchok , Gregory J. Riely , Naiyer A. Rizvi
Background: Thymic epithelial tumors (TETs) are associated with immune dysfunction and are poorly responsive to conventional therapies. We aimed to characterize the immune microenvironment in TETs, to identify potential targets for immunotherapy. Methods: Tumor tissue from 24 TETS was identified. Tumor-infiltrating lymphocytes (TILs: CD3+ and CD8+ T-cells), PD-L1 expression on tumor cells (antibody: E1L3N), and a panel of co-stimulatory (CD137, GITR, OX40, ICOS) and co-inhibitory immune checkpoint molecules (PD-1, CTLA-4, TIM-3) on immune cells, was investigated by immunohistochemistry. PD-L1 positivity was defined as ≥ 25% of tumor cells with positive membranous staining. TILs and immune cell checkpoint molecule staining were semi-quantitatively scored as: low = 0-1, high = 2-3. Associations between clinicopathologic factors, immune checkpoint molecule expression and TILs, was evaluated. Overall survival (OS) was measured from the time of cancer diagnosis, assuming that immune markers do not change throughout the course of disease. Data was analyzed using Fisher’s exact, Wilcoxon rank sum and log-rank tests, and Cox proportional hazards model. Results: Tumor tissue from B2/B3 thymomas (n = 12) and thymic carcinomas (n = 12) was evaluated. CD8+ TILs was seen in all tumors. Sixty-three percent of TETs (n = 15/24) were PD-L1+. PD-L1 positivity was more common in thymomas than thymic carcinomas (11/12 vs. 4/12, p < 0.01). When analyzed as a continuous variable, PD-L1 expression had an inverse correlation with risk of death (p = 0.02). Eighteen pts with TETs (n = 18/24, 75%) had high TIM-3 expression. Two immunologic parameters correlated with improved OS: PD-L1+ tumor cells (p < 0.01) and high TIM-3 expression (p = 0.01). There was a positive correlation between PD-L1+ tumor cells and CD8+ T-cells (p = 0.02), PD-L1+ tumor cells and high TIM-3 expression (p = 0.03), CD8+ T-cells and high TIM-3 expression (p = 0.03). Conclusions: TETs possess a robust TIL infiltrate. The majority of tumors have high expression of the co-inhibitory checkpoint molecule TIM-3, and are PD-L1+. These parameters may correlate with OS. These data support the immunotherapeutic targeting of the PD-1/PD-L1 and TIM-3 pathways in patients with TETs.
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