https://orcid.org/0000-0003-3016-5036
Figures
Abstract
Introduction
Programmed death-ligand 1 (PD-L1) expression in various tumors is known to correlate with the efficacy of immune checkpoint inhibitors; however, evaluation of PD-L1 expression in thymic epithelial tumors (TETs) using multiple antibodies are limited. We retrospectivity evaluated PD-L1 expression in thymomas and thymic carcinomas using two antibodies, SP142 and SP263, and compared their expression rates in each type of TETs.
Materials and methods
We retrospectively included 37 cases of thymoma and 11 cases of thymic carcinoma that were histologically diagnosed between January 2000 and December 2020. PD-L1 expression was assessed using SP142 and SP263 antibodies with semi-quantitative scoring.
Results
The concordance rate for PD-L1 positivity between SP142 and SP263 was 81.2%, whereas the concordance rate for high PD-L1 expression was 83.3%. SP142 showed positive PD-L1 expression in 23 (62%) thymoma cases and eight (73%) thymic carcinoma cases. In contrast, SP263 antibody showed positive PD-L1 expression in 31 (84%) cases of thymoma and 9 (82%) cases of thymic carcinoma. In addition, type B thymomas exhibited significantly higher PD-L1 positivity than other thymoma types. The tumor-infiltrating lymphocytes were mostly CD3 and CD8 positive. No significant difference in overall survival was observed between the high and low PD-L1 expression groups in thymic carcinoma.
Citation: Chubachi K, Tanaka H, Taima K, Tasaka S, Kurose A (2025) PD-L1 expression on tumor cells and tumor-infiltrating immune cells in thymic epithelial tumors detected with SP142 and SP263 antibodies. PLoS One 20(7): e0327792. https://doi.org/10.1371/journal.pone.0327792
Editor: Jun Hyeok Lim, Inha University Hospital, KOREA, REPUBLIC OF
Received: March 24, 2025; Accepted: June 22, 2025; Published: July 9, 2025
Copyright: © 2025 Chubachi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Thymic epithelial tumors (TETs) are rare tumors that arise from the epithelial cells of the thymus and comprise less than 1% of all adult cancers [1,2]. In 2015, the World Health Organization (WHO) classified TETs into 5 types of thymoma (types A, AB, B1, B2, and B3) and thymic carcinoma based on their increasing degree of aggressiveness [1,3]. Complete surgical resection remains the primary curative treatment for patients with early-stage TETs [4–6]. Patients with locally advanced tumors or distant metastases are treated with multimodal therapies, including chemotherapy, surgery, and radiotherapy. TETs are sensitive to platinum-based combination chemotherapy as a first-line therapy [7–9]. However, treatment options after the failure of platinum-based chemotherapy are limited, which is associated with the poor prognosis of TETs.
Recent studies have shown that programmed death-ligand 1 (PD-L1) is expressed in various tumors, including melanoma and ovarian, colon, lung, breast, and renal cell carcinoma [10,11]. Furthermore, it has been shown that PD-L1 expression varies depending on the PD-L1 antibody in various tumors [12–14]. Immunotherapy with antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA4), programmed death-1(PD-1), and PD-L1 has been shown to be clinically effective and is used in treating various types of cancers [15–19]. In addition, PD-L1 expression has also been shown to correlate with efficacy of immune checkpoint inhibitor in several tumors [20,21].
Previous clinical studies demonstrated the efficacy of immune checkpoint inhibitors in TETs [22,23]. Although high PD-L1 expression has been shown in TETs [24–26], most studies have evaluated PD-L1 expression using only a single type of antibody. In addition, there has been no study comparing of PD-L1 expression among histological types of thymoma and thymic carcinoma using multiple types of PD-L1 antibodies. SP142 and SP263 are widely used in clinical practice for various tumors, including non-small cell lung cancer. SP142 can visualize PD-L1 expression not only on tumor cells but also on tumor-infiltrating immune cells. Given the distinct staining characteristics of each clone, the use of these two antibodies may provide complementary information.
In the present study, we evaluated PD-L1 expression in thymomas and thymic carcinomas using two types of antibody clones, SP142 and SP263, and compared the expression rates and examined the prognostic implications of PD-L1 expression.
Materials and methods
Patients
This retrospective study was performed on tumor specimens obtained from 48 consecutive patients diagnosed with thymoma or thymic carcinoma and underwent surgical resection or biopsy at Hirosaki University Hospital between January 2000 and January 2020. Relevant clinical data were collected from medical records. We accessed the medical records or archived samples for research purpose until 31 March 2024. The 2015 WHO classification [3] was used for the histological classification of the TETs. Immune checkpoint inhibitors were not administered in any of the patients. The study was approved by the Ethics Committee of Hirosaki University Graduate School of Medicine (approval no. 2023−071). Informed consent was obtained from all patients using the opt-out method, which was approved by the Ethics Committee of Hirosaki University Graduate School of Medicine (approval no. 2023−071), due to the retrospective nature of the study and the absence of any risk to participants. Detailed information about the study, including the inclusion criteria and the option to opt out, was porvied to patients on the institutional website.
Immunohistochemistry for PD-L1 and tumor-infiltrating immune cells
Formalin-fixed paraffin-embedded (FFPE) tissues were obtained from biopsy specimens or surgically removed tissues. An FFPE block of surgical specimens was selected from a centrally located area of the tumor. Each tissue specimen was histologically confirmed to contain tumor cells using hematoxylin and eosin staining. FFPE tissues were sectioned at 4 μm, deparaffinized, rehydrated, and subjected to immunohistochemistry using an automated system (Ventana Benchmark ULTRA System; Roche, Tucson, AZ, USA) with commercially available detection kits and antibodies against PD-L1 (PD-L1 Ventana SP142 and PD-L1 Ventana SP263 assay kits, Ventana Medical Systems, Tucson, AZ, USA). Since a standardized evaluation method for PD-L1 expression in TETs has not yet been established, PD-L1 expression in the present study was assessed based on the criteria reported in clinical trials of non-small cell lung cancer using SP142 and SP263 antibodies [27,28]. Two independent observers (KC and AK) performed semi-quantitative scoring based on the percentage of tumor cells showing positivity on the cell membranes. This was also performed for tumor-infiltrating immune cells based on the percentage of cells that were positive, regardless of staining intensity. Specifically, for SP142, < 1%, 1%−4%, 5%−49%, and 50% ≤ positivity were categorized as TC0, TC1, TC2, and TC3, respectively. TC3 was defined as high PD-L1 expression. For SP263 expression, < 1%, 1%−49%, and 50% ≤ positivity were categorized as negative, low, and high, respectively. For tumor-infiltrating immune cells, using SP142, < 1%, 1%–4%, 5%–9%, and 10% ≤ positivity in the tumor area were defined as IC0, IC1, IC2, and IC3, respectively.
Statistical analyses
Categorical data were expressed as frequencies and percentages, and quantitative data were expressed as medians (range). Fisher’s exact test was used to evaluate the statistical significance of the data. A two-tailed p < 0.05 denoted a statistically significant difference. Survival curves were generated using the Kaplan–Meier method, and the log-rank test was used to assess the statistical significance of differences among the groups. All statistical analyses were performed using the JMP software program (version 16.0.0, SAS Institute, Tokyo, Japan).
Results
Patient characteristics
We examined 37 cases of thymoma and 11 cases of thymic carcinoma. Table 1 shows the patients’ characteristics. The histological types of thymoma were type A in 6 cases, type AB in 12, type B1 in 4, type B2 in 12, and type B3 in 3. The histological type of thymic carcinoma was squamous cell carcinoma in 9 cases, basaloid cell carcinoma in 1, and undifferentiated carcinoma in 1. These cases included all stages of Masaoka classification, with a predominance of early-stage cases. Specimen sampling was performed by surgical resection in 45 cases and CT-guided needle biopsy in 3 cases. Postoperative recurrence occurred in 7 cases of thymoma and 6 cases of thymic carcinoma, all of which were treated subsequently with chemotherapy. Death was observed in 4 cases of thymoma and 5 cases of thymic carcinoma.
Expression of PD-L1 in tumor cells
The results of PD-L1 reactivity with SP142 and SP263 in thymoma and thymic carcinoma tumor cells are shown in Fig 1 and Table 2. The concordance rate for PD-L1 positivity between SP142 and SP263 was 81.2%, while the concordance rate for high PD-L1 expression was 83.3% (Table 3). A high PD-L1 positive rate was observed in both diseases. Furthermore, in type B thymoma, PD-L1 positivity rate was 84% with SP142 and 95% with SP263 (Fig 2B), and the rate showing high PD-L1 expression was 47% for SP142 and 79% for SP263 (Table 4). PD-L1 was mainly expressed on the membrane of the tumor cells in both diseases (Fig 1M-N). However, the intensity of reactivity varied from weak to strong, and homogeneity varied among the patients. Comparing the PD-L1 positivity between SP142 and SP263, the PD-L1 positivity was higher with SP263 in both thymoma and thymic carcinoma. (thymoma: p = 0.0013; thymic carcinoma: p = 0.0545, Fig 2A). In comparison to other types of thymoma, PD-L1 positivity of type B was higher with either antibody, and a significant difference in positivity rate was observed between SP142 (SP142: p = 0.0069; SP263: p = 0.0897, Fig 2B).
(A–C): In a type A thymoma, PD-L1 positivity with SP142 was less than 1% in tumor cells (TC0) and 1% in tumor-infiltration immune cells (IC1), while it was 5% in tumor cells (low expression) with SP263. (D–F): In a type AB thymoma, PD-L1 positivity with SP142 was 1% in tumor cells (TC1) and 10% in tumor-infiltration immune cells (IC2), while with SP263, it was 5% in tumor cells (low expression). (G–I): In a type B2 thymoma, PD-L1 positivity with SP142 was 20% in tumor cells (TC2) and 5% in tumor-infiltration immune cells (IC1), while with SP263, it was 60% in tumor cells (high expression). (J–L): In a thymic carcinoma, PD-L1 positivity with SP142 was 70% in tumor cells (TC3) and 70% in tumor-infiltration immune cells (IC3), while with SP263, it was 90% in tumor cells (high expression). (M, N): PD-L1 was mainly expressed on the membrane of the tumor cells (M: SP142, type B2 thymoma; N: SP263, thymic carcinoma).
Expression of PD-L1 in tumor-infiltrating immune cells
The results of PD-L1 positivity rate in tumor-infiltrating immune cells with SP142 are shown in Table 5. Both thymoma and thymic carcinoma showed a high population of high PD-L1 expression (IC3) in tumor-infiltrating immune cells. However, PD-L1 expression was not observed in four (10.8%) cases of thymoma and three (27.3%) cases of thymic carcinoma. In addition, among the cases evaluated with SP142, cases classified as IC3 but TC0–2 were identified in nine thymoma cases and three thymic carcinoma cases.
Clinical outcome according to PD-L1 expression
Because mortality events were observed only in 4 (10.8%) cases of thymoma, survival analysis based on PD-L1 expression in thymomas was not feasible in the present study. On the other hand, 5 (45.5%) of 11 patients with thymic carcinoma were deceased. Overall survival curves for all thymic carcinoma cases, comparing high or low/negative PD-L1 expression, are shown in Fig 3. The median overall survival was not reached (95% confidence interval [CI]: 22.9–not reached), and the 5-year survival rate was 50.9% (Fig 3A). The median survival in the high PD-L1 expression group was 49.5 months (95% CI: 27.5–not reached), whereas in the low/negative PD-L1 expression group, it was 22.9 months (95% CI: 8.13–not reached) (Fig 3B). Although a trend toward longer survival was observed in the high PD-L1 expression group, no significant difference was observed between the two groups (p = 0.3549).
(A): All patients with thymic carcinoma. (B): Comparison between patients with high PD-L1 expression and those with low/negative expression (p = 0.3549, log-rank test).
Discussion
In the present study, PD-L1 positivity was high in TETs, and more than half of the cases of either thymomas and thymic carcinomas showed high PD-L1 expression. PD-L1 expression rates differed depending on the PD-L1 antibodies. Furthermore, in thymomas, a significant difference in PD-L1 positivity with SP142 was observed between type B2 and other histological types.
PD-L1 is a transmembrane protein and an immune checkpoint molecule that mitigates excessive immune responses and attacks on normal cells. PD-L1 is widely expressed in immune cells, such as T and B cells, macrophages, regulatory T cells, and dendritic cells, as well as in many human cancer cells and virus-infected cells [11,29,30]. The thymus plays a central role in the development of immunocompetent T cells and their tolerance mechanisms [31]. Normal thymic tissue comprises immune cells, such as numerous T cell lymphocytes, macrophages, and epithelial cells. It has been reported that PD-L1 expression in thymic epithelial cells is observed in normal fetal thymus and non-tumorous thymic tissue through immunohistochemistry [24,32,33]. Furthermore, similar expression patterns have been reported in type B2 thymoma, suggesting that PD-L1 expression in thymomas may reflect the biological characteristics of the thymus [34]. However, the significance of PD-L1 expression in the thymic tissue and thymic epithelial tumors remains unclear.
There have been 14 studies of PD-L1 expression in TETs using PD-L1 antibodies. As summarized in Table 6 [24–26,34–44], TETs showed high PD-L1 positivity, which is compatible with the results of the present study. However, these previous reports showed a wide range of PD-L1 expression: 27%–98% in thymoma and 14%–100% in thymic carcinoma, possibly because different antibodies were used in the studies. Among the commercially available PD-L1 antibodies, SP263 antibody showed PD-L1 positivity in lung cancer equivalent to 22C3 or 28−8 antibodies, whereas SP142 antibody was reported to have the lowest PD-L1 positivity [45–47]. Sakane et al. examined that PD-L1 expression using SP142, SP263, 22C3, and 28−8 antibodies in thymomas and found no difference [42]. Rouquette et al. examined PD-L1 expression in thymoma types B2 and B3 and thymic carcinomas using SP142, SP263, 22C3, and E1L3N antibodies. They reported that PD-L1 expression was lowest with SP142 antibody [26]. In the present study, the PD-L1 expression detected using SP263 antibody was significantly higher than that detected using SP142 antibody, which is compatible with the results of previous reports. However, no universally established method exists for evaluating PD-L1 expression in TETs, and it remains unclear which antibody is most appropriate.
Tumor-infiltrating immune cells are important components of the tumor microenvironment, influencing tumor progression, metastasis, and response to therapy. Among these, CD8 ⁺ cytotoxic T cells have been particularly associated with favorable prognosis in many tumor types due to their ability to recognize and eliminate tumor cells [48]. PD-L1, expressed on tumor-infiltrating immune cells, interacts with the PD-1 receptor on T cells to inhibit T cell activation and promote immune evasion. PD-L1 inhibitors restore T cell function by disrupting this interaction, leading to enhanced antitumor responses [49]. In our study, PD-L1-positive immune cells were more frequently observed in thymomas than in thymic carcinomas. However, higher levels of PD-L1 expression on tumor-infiltrating immune cells were observed in thymic carcinomas. Moreover, PD-L1 expression in tumor-infiltrating immune cells was higher in type B3 thymomas compared with thymic carcinomas, which may be attributable to morphological differences [26]. Furthermore, Shukuya et al. evaluated the efficacy of chemotherapy combined with immune checkpoint inhibitors in patients with thymic carcinoma and reported that higher PD-L1 expression in tumor-infiltrating immune cells was associated with an improved treatment response [50]. These findings underscore the importance of assessing PD-L1 expression in tumor-infiltrating immune cells when devising immunotherapeutic strategies for TETs.
The correlation between PD-L1 expression and prognosis in TETs is still controversial [33,38,40,50,51]. In the present study, survival curve analysis based on PD-L1 expression in thymic carcinoma showed a trend toward longer survival in the group with high PD-L1 expression, although no statistically significant difference was observed (Fig 3B). Yokoyama et al. reported that thymic carcinoma with high PD-L1 expression had a better prognosis than those with low expression [51]. On the contrary, Funaki et al. reported that patients with thymic carcinoma with high PD-L1 expression had a poor prognosis [38]. Furthermore, several reports showed no correlation between PD-L1 expression and survival [25,52,53]. Although TETs are known to have a low tumor mutation burden (TMB) [54,55], which is generally associated with reduced immunogenicity, favorable responses to immune checkpoint inhibitors have been reported in clinical trials. Giaccone et al. evaluated PD-L1 expression in 40 patients with thymic carcinoma who showed disease progression after at least one line of pembrolizumab treatment [23]. The overall response rate for pembrolizumab was 22.5%. In their study, 22C3 was used as the PD-L1 antibody, and a better response was observed in patients with high PD-L1 expression. In another phase II trial by Cho et al., 33 patients with TETs, including 26 with thymic carcinoma and seven with thymoma, were treated with pembrolizumab. The response rates in patients with thymic carcinoma and thymoma were 19.2% and 28.6%, respectively. However, grade 3 or higher immune-related adverse events were observed in 71.4% of patients with thymoma [22]. In a clinical trial by Katsuya et al. including 15 patients with thymic carcinoma, the overall response rate was 0%; however, disease control was achieved in 11 patients. PD-L1 expression was not evaluated in this study [56]. These findings suggest that immune checkpoint inhibitors may be effective in TETs, and that PD-L1 expression may serve as a valuable predictive biomarker for the efficacy of immune checkpoint inhibitors. However, due to the high incidence of severe immune-related adverse events, particularly in thymoma, careful risk assessment is warranted. Furthermore, a recent review by Lucà et al. has highlighted the importance of tissue-based biomarkers such as PD-L1 and tumor-infiltrating immune cells in guiding the use of immune checkpoint inhibitors in TETs [57]. Incorporating these biomarkers may facilitate a more personalized and safer use of immune checkpoint inhibitors in TETs.
Our study had several limitations. First, the sample size was small due to the single-center retrospective nature of the study. Future studies should include larger numbers of cases from multiple institutions. Second, antibodies other than those used in this study are available to assess PD-L1 expression, and there is variability in positive rates and cut-off values among different antibodies. In addition, the cut-off values used in this study were based on criteria established for lung cancer. Although many previous reports have identified a tumor proportion score (TPS) ≥ 1% as positive, this is not a clearly established criterion for TETs. Furthermore, differences in scoring methods between SP142 and SP263 may introduce bias in the comparison of PD-L1 expression between the two antibodies. Lastly, the follow-up time for prognostic analysis might not be sufficient, with particularly few mortality events in thymomas, making survival analysis unfeasible.
Conclusion
This study evaluated PD-L1 expression in TETs comparing two antibodies, SP142 and SP263, which are different from those used in previous reports: PD-L1 positivity was high in TETs. More than half of both thymomas and thymic carcinomas showed high PD-L1 expression, although the PD-L1 positivity was different between the two commercially available PD-L1 antibodies and among histological types of TETs. PD-L1 expression was high with both antibodies in some TETs. SP263 showed higher PD-L1 expression rate compared to SP142, indicating that it may be more appropriate for the detection of PD-L1. It is important to consider the difference among PD-L1 antibodies for each histological type of TETs. In the present study, no significant correlation was observed between PD-L1 expression and survival of the patients. Further research is required to establish standardized methods for evaluating PD-L1 expression and its prognostic implication in TETs.
Supporting information
S1 Table. Clinicopathologic Characteristics and PD-L1 expression of patients with thymic epithelial tumors.
https://doi.org/10.1371/journal.pone.0327792.s001
(XLSX)
References
- 1. Girard N, Ruffini E, Marx A, Faivre-Finn C, Peters S; ESMO Guidelines Committee. Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26 Suppl 5:v40–55. pmid:26314779
- 2. de Jong WK, Blaauwgeers JLG, Schaapveld M, Timens W, Klinkenberg TJ, Groen HJM. Thymic epithelial tumours: a population-based study of the incidence, diagnostic procedures and therapy. Eur J Cancer. 2008;44(1):123–30. pmid:18068351
- 3.
Cote W. Thoracic tumours. International Agency for Research on Cancer. 2021.
- 4. Girard N, Lal R, Wakelee H, Riely GJ, Loehrer PJ. Chemotherapy definitions and policies for thymic malignancies. J Thorac Oncol. 2011;6(7 Suppl 3):S1749-55. pmid:21847058
- 5. Schmitt J, Loehrer PJ Sr. The role of chemotherapy in advanced thymoma. J Thorac Oncol. 2010;5(10 Suppl 4):S357-60. pmid:20859133
- 6. Zhao Y, Shi J, Fan L, Hu D, Yang J, Zhao H. Surgical treatment of thymoma: an 11-year experience with 761 patients. Eur J Cardiothorac Surg. 2016;49(4):1144–9. pmid:26324679
- 7. Thomas CR, Wright CD, Loehrer PJ. Thymoma: state of the art. J Clin Oncol. 1999;17(7):2280–9. pmid:10561285
- 8. Margaritora S, Cesario A, Cusumano G, Meacci E, D’Angelillo R, Bonassi S, et al. Thirty-five-year follow-up analysis of clinical and pathologic outcomes of thymoma surgery. Ann Thorac Surg. 2010;89(1):245–52; discussion 252. pmid:20103246
- 9. Loehrer PJ Sr, Kim K, Aisner SC, Livingston R, Einhorn LH, Johnson D, et al. Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol. 1994;12(6):1164–8. pmid:8201378
- 10. Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res. 2006;66(7):3381–5. pmid:16585157
- 11. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800. pmid:12091876
- 12. Karnik T, Kimler BF, Fan F, Tawfik O. PD-L1 in breast cancer: comparative analysis of 3 different antibodies. Hum Pathol. 2018;72:28–34. pmid:28843709
- 13. Naso JR, Wang G, Banyi N, Derakhshan F, Shokoohi A, Ho C, et al. Comparability of laboratory-developed and commercial PD-L1 assays in non-small cell lung carcinoma. Ann Diagn Pathol. 2021;50:151590. pmid:33157383
- 14. Palicelli A, Bonacini M, Croci S, Magi-Galluzzi C, Cañete-Portillo S, Chaux A, et al. What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 1: Focus on Immunohistochemical Results with Discussion of Pre-Analytical and Interpretation Variables. Cells. 2021;10(11):3166. pmid:34831389
- 15. Herbst RS, Soria J-C, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–7. pmid:25428504
- 16. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54. pmid:22658127
- 17. Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65. pmid:22658128
- 18. Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16(3):257–65. pmid:25704439
- 19. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33. pmid:23724867
- 20. Wang X, Teng F, Kong L, Yu J. PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther. 2016;9:5023–39. pmid:27574444
- 21. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823–33. pmid:27718847
- 22. Cho J, Kim HS, Ku BM, Choi Y-L, Cristescu R, Han J, et al. Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial. J Clin Oncol. 2019;37(24):2162–70. pmid:29906252
- 23. Giaccone G, Kim C, Thompson J, McGuire C, Kallakury B, Chahine JJ, et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol. 2018;19(3):347–55. pmid:29395863
- 24. Marchevsky AM, Walts AE. PD-L1, PD-1, CD4, and CD8 expression in neoplastic and nonneoplastic thymus. Hum Pathol. 2017;60:16–23. pmid:27746267
- 25. Owen D, Chu B, Lehman AM, Annamalai L, Yearley JH, Shilo K, et al. Expression Patterns, Prognostic Value, and Intratumoral Heterogeneity of PD-L1 and PD-1 in Thymoma and Thymic Carcinoma. J Thorac Oncol. 2018;13(8):1204–12. pmid:29702286
- 26. Rouquette I, Taranchon-Clermont E, Gilhodes J, Bluthgen M-V, Perallon R, Chalabreysse L, et al. Immune biomarkers in thymic epithelial tumors: expression patterns, prognostic value and comparison of diagnostic tests for PD-L1. Biomark Res. 2019;7:28. pmid:31827799
- 27. Felip E, Altorki N, Zhou C, Csőszi T, Vynnychenko I, Goloborodko O, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021;398(10308):1344–57. pmid:34555333
- 28. Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, et al. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med. 2020;383(14):1328–39. pmid:32997907
- 29. Guan J, Lim KS, Mekhail T, Chang C-C. Programmed Death Ligand-1 (PD-L1) Expression in the Programmed Death Receptor-1 (PD-1)/PD-L1 Blockade: A Key Player Against Various Cancers. Arch Pathol Lab Med. 2017;141(6):851–61. pmid:28418281
- 30. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239–45. pmid:17304234
- 31. Shi Y, Zhu M. Medullary thymic epithelial cells, the indispensable player in central tolerance. Sci China Life Sci. 2013;56(5):392–8. pmid:23633070
- 32. Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol. 2003;170(3):1257–66. pmid:12538684
- 33. Padda SK, Riess JW, Schwartz EJ, Tian L, Kohrt HE, Neal JW, et al. Diffuse high intensity PD-L1 staining in thymic epithelial tumors. J Thorac Oncol. 2015;10(3):500–8. pmid:25402569
- 34. Ishihara S, Okada S, Ogi H, Kodama Y, Shimomura M, Tsunezuka H, et al. Programmed death-ligand 1 expression profiling in thymic epithelial cell tumors: Clinicopathological features and quantitative digital image analyses. Lung Cancer. 2020;145:40–7. pmid:32402921
- 35. Bedekovics J, Beke L, Mokanszki A, Szilagyi S, Mehes G. Programmed Death-ligand 1 (PD-L1) Expression in Thymic Epithelial Tumors. Appl Immunohistochem Mol Morphol. 2020;28(1):1–9. pmid:30499814
- 36. Berardi R, Goteri G, Brunelli A, Pagliaretta S, Paolucci V, Caramanti M, et al. Prognostic relevance of programmed cell death protein 1/programmed death-ligand 1 pathway in thymic malignancies with combined immunohistochemical and biomolecular approach. Expert Opin Ther Targets. 2020;24(9):937–43. pmid:32662701
- 37. Chen Y, Zhang Y, Chai X, Gao J, Chen G, Zhang W, et al. Correlation between the Expression of PD-L1 and Clinicopathological Features in Patients with Thymic Epithelial Tumors. Biomed Res Int. 2018;2018:5830547. pmid:29850538
- 38. Funaki S, Shintani Y, Fukui E, Yamamoto Y, Kanzaki R, Ose N, et al. The prognostic impact of programmed cell death 1 and its ligand and the correlation with epithelial-mesenchymal transition in thymic carcinoma. Cancer Med. 2019;8(1):216–26. pmid:30600651
- 39. Guleria P, Husain N, Shukla S, Kumar S, Parshad R, Jain D. PD-L1 immuno-expression assay in thymomas: Study of 84 cases and review of literature. Ann Diagn Pathol. 2018;34:135–41. pmid:29661720
- 40. Hakiri S, Fukui T, Mori S, Kawaguchi K, Nakamura S, Ozeki N, et al. Clinicopathologic Features of Thymoma With the Expression of Programmed Death Ligand 1. Ann Thorac Surg. 2019;107(2):418–24.https://doi.org/10.1016/j.athoracsur.2018.08.037 pmid:30312607.
- 41. Higuchi R, Goto T, Hirotsu Y, Nakagomi T, Yokoyama Y, Otake S, et al. PD-L1 Expression and Tumor-Infiltrating Lymphocytes in Thymic Epithelial Neoplasms. J Clin Med. 2019;8(11):1833. pmid:31683962
- 42. Sakane T, Murase T, Okuda K, Takino H, Masaki A, Oda R, et al. A comparative study of PD-L1 immunohistochemical assays with four reliable antibodies in thymic carcinoma. Oncotarget. 2018;9(6):6993–7009. pmid:29467945
- 43. Song JS, Kim D, Kwon JH, Kim HR, Choi C-M, Jang SJ. Clinicopathologic Significance and Immunogenomic Analysis of Programmed Death-Ligand 1 (PD-L1) and Programmed Death 1 (PD-1) Expression in Thymic Epithelial Tumors. Front Oncol. 2019;9:1055. pmid:31681591
- 44. Wang H, Xu X, Luo L, Wang C, Jiang Z, Lin Y. Mutational landscape of thymic epithelial tumors in a Chinese population: insights into potential clinical implications. Gland Surg. 2021;10(4):1410–7. pmid:33968692
- 45. Hirsch FR, McElhinny A, Stanforth D, Ranger-Moore J, Jansson M, Kulangara K, et al. PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project. J Thorac Oncol. 2017;12(2):208–22. pmid:27913228
- 46. Rimm DL, Han G, Taube JM, Yi ES, Bridge JA, Flieder DB, et al. A Prospective, Multi-institutional, Pathologist-Based Assessment of 4 Immunohistochemistry Assays for PD-L1 Expression in Non-Small Cell Lung Cancer. JAMA Oncol. 2017;3(8):1051–8. pmid:28278348
- 47. Tsao MS, Kerr KM, Kockx M, Beasley M-B, Borczuk AC, Botling J, et al. PD-L1 Immunohistochemistry Comparability Study in Real-Life Clinical Samples: Results of Blueprint Phase 2 Project. J Thorac Oncol. 2018;13(9):1302–11. pmid:29800747
- 48. Lin X, Kang K, Chen P, Zeng Z, Li G, Xiong W, et al. Regulatory mechanisms of PD-1/PD-L1 in cancers. Mol Cancer. 2024;23(1):108. pmid:38762484
- 49. Yi M, Niu M, Xu L, Luo S, Wu K. Regulation of PD-L1 expression in the tumor microenvironment. J Hematol Oncol. 2021;14(1):10. pmid:33413496
- 50. Arbour KC, Naidoo J, Steele KE, Ni A, Moreira AL, Rekhtman N, et al. Expression of PD-L1 and other immunotherapeutic targets in thymic epithelial tumors. PLoS One. 2017;12(8):e0182665. pmid:28771603
- 51. Yokoyama S, Miyoshi H, Nishi T, Hashiguchi T, Mitsuoka M, Takamori S, et al. Clinicopathologic and Prognostic Implications of Programmed Death Ligand 1 Expression in Thymoma. Ann Thorac Surg. 2016;101(4):1361–9. pmid:26794891
- 52. Tiseo M, Damato A, Longo L, Barbieri F, Bertolini F, Stefani A, et al. Analysis of a panel of druggable gene mutations and of ALK and PD-L1 expression in a series of thymic epithelial tumors (TETs). Lung Cancer. 2017;104:24–30. pmid:28212996
- 53. Wei Y-F, Chu C-Y, Chang C-C, Lin S-H, Su W-C, Tseng Y-L, et al. Different pattern of PD-L1, IDO, and FOXP3 Tregs expression with survival in thymoma and thymic carcinoma. Lung Cancer. 2018;125:35–42. pmid:30429036
- 54. Radovich M, Pickering CR, Felau I, Ha G, Zhang H, Jo H, et al. The Integrated Genomic Landscape of Thymic Epithelial Tumors. Cancer Cell. 2018;33(2):244-258.e10. pmid:29438696
- 55. Wang Y, Thomas A, Lau C, Rajan A, Zhu Y, Killian JK, et al. Mutations of epigenetic regulatory genes are common in thymic carcinomas. Sci Rep. 2014;4:7336. pmid:25482724
- 56. Katsuya Y, Horinouchi H, Seto T, Umemura S, Hosomi Y, Satouchi M, et al. Single-arm, multicentre, phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study. Eur J Cancer. 2019;113:78–86. pmid:30991261
- 57. Lucà S, Accardo M, Campione S, Franco R. Immunotherapy in thymic epithelial tumors: tissue predictive biomarkers for immune checkpoint inhibitors. Explor Target Antitumor Ther. 2024;5(3):465–76. pmid:38966177