Clinicopathologic Significance and Immunogenomic Analysis of Programmed Death-Ligand 1 (PD-L1) and Programmed Death 1 (PD-1) Expression in Thymic Epithelial Tumors

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.

Difference in the distribution of tumor‐infiltrating CD8+ T cells and FOXP3+ T cells between micronodular thymoma with lymphoid stroma and micronodular thymic carcinoma with lymphoid stroma

“…PD‐L1 binds to PD‐1 on CD8 (+) T cells and suppresses tumor immune response 35 . Several studies focusing on PD‐L1 expression in tumor cells of thymic epithelial neoplasms have shown that the PD‐L1‐positivity rate in the tumor cells tends to be higher in type B thymoma and thymic SCC cases than in type A or AB thymoma cases 34,36–43 . The results of PD‐L1 expression in typical thymoma and thymic SCC cases of the present study are similar to those obtained in previous studies.…”

The Expression of PD-L1 and B7-H4 in Thymic Epithelial Tumor and Its Relationship With Tumor Immune-Infiltrating Cells

“…The results of this study showed that patients with high-grade TET (type C) have higher PD-L1 expression than patients with type A/B TET, which was consist with the results of several studies. We reviewed and summarized 17 published research results on PD-L1 expression in TET, which were listed in Table 6 (9)(10)(11)(12)(13)(14)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). From these studies, six studies showed that PD-L1 expression is related to Masaoka stage (9, 11-13, 32, 41) and 10 studies showed that PD-L1 expression is related to WHO pathological classification (9-13, 32, 36, 40, 41).…”

Induction Strategy for Locally Advanced Thymoma

“…The most commonly used predictor for Programmed Cell Death-1/ Programmed Cell Death-Ligand 1 (PD-1/PD-L1) immune therapy is the expression of PD-L1 (49,50). As reported, high expression of PD-L1, being statistically associated with more aggressive histological types, higher Masaoka-Koga stages and even worse prognosis (51)(52)(53)(54), was observed in 23%-92% thymoma patients (52,(55)(56)(57)(58)(59)(60)(61). In addition, tumor-infiltrating lymphocytes, which are required for adequate activation of immune system, were diffusely and abundantly distributed in thymoma cases (60,62).…”