Prognostic Significance of Programmed Death Ligand 1 Expression and Tumor-Infiltrating Lymphocytes in Axial Osteosarcoma

OBJECTIVE: To characterize the intratumoral immune microenvironment and evaluate its clinical implications in patients with primary axial osteosarcoma. METHODS: Immunohistochemistry was used to interpret tumor programmed death ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) profile of cluster of differentiation 8 (CD8), PD-L1, and programmed death 1 (PD-1) within 69 tumor specimens. RESULTS: Overall, all tumor specimens presented lymphocytic infiltrates, with PD-L1+ TILs being the most common subset (mean, 215.1 per slide mm(2)). Positive tumor PD-L1 expression was presented in 43.5% of tumors. Moderate to strong relationships were detected among TILs subsets and tumor PD-L1 expression. In addition, the density of PD-L1+ TILs was significantly correlated with favorable clinicopathologic features, including earlier Enneking stage. The positivity of tumor PD-L1 expression was associated with the tumor site and pathologic grade (P = 0.021 and 0.037, respectively). In univariate survival analysis, the high density of PD-L1+ TILs or CD8+ TILs was significantly correlated with both prolonged event-free survival and overall survival (OS), whereas the high infiltration of PD-1+ TILs was significantly associated with reduced OS, as was the positive tumor PD-L1 expression. Furthermore, multivariate analysis showed that CD8+ TILs and PD-L1+ TILs remained their significance for both event-free survival (P = 0.012 and 0.004, respectively) and OS (P = 0.033 and 0.002, respectively). However, both PD-1+ TILs and tumor PD-L1 expression failed to reach significance for OS. CONCLUSIONS: Our results suggested that the immune microenvironment is of clinically relevant significance in patients with axial osteosarcoma. Specifically, we identified both PD-L1+ TILs and CD8+ TILs as independent favorable prognostic markers.