Abstract
Objectives: Thymic epithelial tumors (TETs) are rare malignant tumors that exhibit heterogeneous histology and clinical behavior. As immune check point inhibitors, drugs targeting anti-programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have shown remarkable results against many cancers; thus, the importance of PD-1/PD-L1 immunohistochemistry as a predictive or prognostic biomarker has grown. However, limited data on PD-L1 and PD-1 expression in TETs have been reported; moreover, these results have been variable. Here, we examined the expression of PD-1/PD-L1 proteins in TETs and analyzed the clinicopathologic significance of this expression.Patients and Methods: A tissue microarray was constructed using 368 samples of TETs, each in triplicate. Immunohistochemistry for PD-L1 (SP263 assay) and PD-1 in TETs and CD8 in thymic carcinoma (TC) was performed; next, correlations with clinicopathologic characteristics were analyzed. PD-L1high was designated as ≥50% of tumor proportion score; PD-1high and CD8high were defined as ≥5% and 1% of tumoral immune cells, respectively.Results: The cohort consisted of 308 patients with thymomas and 60 patients with TC. PD-L1 positivity was identified in 90.6% (328/362, ≥1%) of TETs, PD-1 expression of intra-/peritumoral T cells was identified in 53.6% (194/362) of TETs and CD8 positivity was identified in 11% (7/60, ≥1%) of TC. Of the 362 patients, 141 (39.0%) exhibited high PD-L1 expression (PD-L1high). The PD-L1high thymoma group was correlated with high Masaoka-Koga stage (p < 0.001), type B3 histology (p < 0.001), and myasthenia gravis (p < 0.001). This group exhibited poor overall survival (OS, p = 0.003, log-rank) and worse disease-free survival (DFS, p = 0.042, log-rank). No survival differences were detected between PD-L1high and PD-L1low groups in TC. Additionally, there was no correlation between PD-1 expression and survival in patients with TETs. Multivariate analysis revealed that PD-L1high expression was an independent poor prognostic factor (p = 0.047, HR 2.087, 95% CI, 1.009–4.318) in thymomas.Conclusions: To our knowledge, this is the largest study on TETs published in English literature. This study provides useful information regarding the prognosis of and potential therapeutic options for patients with TETs.
Highlights
The thymus is primarily a lymphoid organ in which T lymphocytes mature as a component of the adaptive immune system function
We evaluated Programmed death-ligand 1 (PD-L1) expression using a scoring system with various cut-offs (1, 5, 10, 25, and 50%) based on a previously described proportion score (Cologne score) [15], as there were no established criteria for PD-L1 in Thymic epithelial tumors (TETs)
Among 302 patients with thymomas, immuno-positivity for PD-L1 was
Summary
The thymus is primarily a lymphoid organ in which T lymphocytes mature as a component of the adaptive immune system function. The binding of PD-L1 to its receptor, programmed cell death protein 1 (PD-1), inhibits activated T cell proliferation in peripheral tissues leading to “T cell exhaustion,” a T cell hypo-reactive condition [4]. Based on this mechanism, anti-PD-1/PD-L1 drugs have been used to treat many tumor types, including melanoma, non-small cell lung cancer (NSCLC), and head and neck cancers; the applications of these drugs have been gradually expanded to other tumor types [5,6,7]. Various methods to analyze several other candidate biomarkers related to tumor immunology are under development; immunohistochemistry for PD-L1 is the prevalent method
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