Expression Patterns, Prognostic Value, and Intratumoral Heterogeneity of PD-L1 and PD-1 in Thymoma and Thymic Carcinoma

Owen, Dwight H.; Chu, Benjamin F.; Lehman, Amy; Annamalai, Lakshmanan; Yearley, Jennifer H.; Shilo, Konstantin; Otterson, Gregory A.

doi:10.1016/j.jtho.2018.04.013

Cited by 48 publications

(43 citation statements)

References 56 publications

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“…However, limited information is currently available on CD4 and CD8 single-positive T cells in TETs for anti-tumor immunotherapy. Previous studies were based on immunohistochemical findings, including PD-1 and PD-L1 staining [13][14][15][16] , which limited analyses of the multiple molecular profiles of T cells. Regarding T-cell immune profiles, a flow cytometric analysis provides powerful options 17 .…”

Section: Discussionmentioning

confidence: 99%

Immunotherapeutic potential of CD4 and CD8 single-positive T cells in thymic epithelial tumors

Yamamoto

Iwahori

Funaki

et al. 2020

Sci Rep

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Indications for current immune checkpoint inhibitors are expanding and now include thymic epithelial tumors (TETs). Although clinical trials on immune checkpoint inhibitors for TETs are ongoing, a rationalehas not yet been established for immunotherapy for TETs. Therefore, we herein performed phenotypic and functional analyses of T cells in surgically resected TET tissues with a focus on the anti-tumor properties of T cells to TETs as a step towards establishing a rationale for immunotherapy for TETs. We examined T-cell profiles in surgically resected TET tissues, particularly CD4 and CD8 single-positive T cells, using flow cytometry. In the functional analysis of T cells in TETs, we investigated not only cytokine production by T cells, but also their cytotoxicity using bispecific T-cell engager technology. The cluster analysis of T-cell profiles based on flow cytometric data revealed that type B3 thymoma and thymic carcinoma (B3/C) belonged to the hot cluster characterized by a high proportion of Tim-3+ and CD103+ in CD4 and CD8 single-positive T cells. Enhancements in cytokine production and the cytotoxicity of T cells by the anti-PD-1 antibody were significantly greater in B3/C. These results indicate the potential of immunotherapy for patients with B3/C.Most anterior mediastinal tumors are thymic epithelial tumors (TETs) including thymoma and thymic carcinoma, which originate in the thymus. According to the World Health Organization (WHO) histopathological classification, TETs are classified as thymoma (types A, AB, B1, B2, and B3) or thymic carcinoma (type C in the 2004 classification) based on the morphology of epithelial tumor cells and the extent of intratumor lymphocytic involvement 1-3 . The complexity, rarity, and heterogeneity of this disease and the lack of in vitro and in vivo models make it difficult to develop standard treatments. Complete surgical resection is reportedly the only chance for a cure in TETs 4,5 . However, even after complete resection, the recurrence rates of type B3 and type C thymoma (thymic carcinoma) are 27 and 50%, respectively 6 . Surgery cannot be indicated for some patients when tumors invade the surrounding organs, such as the heart and great vessels, and metastasize to multiple organs. More aggressive histological types of TETs often present at an advanced stage and result in worse overall survival. Chemotherapy, radiation therapy, and molecular-targeting agents are also options in combinatorial treatment strategies 7,8 .Immune checkpoint inhibitors began a new era in cancer immunotherapy. The anti-PD-1 blocking antibody exerts beneficial effects in a limited population of cancer patients 9 . Indications for the anti-PD-1 blocking antibody are expanding and now include TETs. Clinical trials on immune checkpoint inhibitors are ongoing, and acceptable clinical efficacies of the anti-PD-1 antibody have been reported for TETs 10,11 . In the development of anti-PD-1 therapy for TETs, it is crucial to establish a method that identifies target patients who are more likely to res...

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Section: Discussionmentioning

confidence: 99%

Immunotherapeutic potential of CD4 and CD8 single-positive T cells in thymic epithelial tumors

Yamamoto

Iwahori

Funaki

et al. 2020

Sci Rep

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“…The analysis of the association between PD-L1 expression and overall survival (OS) included four studies with 555 TET patients. Hakiri et al 7 and Song et al 1 reported the HR in thymoma, Owen et al 8 in TC, and Wei et al 3 in both. This analysis was performed to include each HR reported in Wei et al 3 The pooled HR was evaluated using a fixed effect model (I 2 = 24.5%, P = 0.258).…”

Section: Association Between Pd-l1 Expression and Overall Survivalmentioning

confidence: 98%

“…6 Several studies have also shown an association between PD-L1 expression and prognosis of patients diagnosed with TETs. 1,3,4,[7][8][9] However, the association of PD-L1 expression with the prognosis of TETs has not yet been systematically analyzed.…”

Section: Introductionmentioning

confidence: 99%

Prognostic and clinicopathological roles of programmed death‐ligand 1 (PD‐L1) expression in thymic epithelial tumors: A meta‐analysis

et al. 2020

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Background Programmed death‐ligand 1 (PD‐L1) is one of the immune checkpoint proteins, and plays an important role in the progression and microenvironment of cancer. PD‐L1 expression has been associated with poor survival in many cancers. Several studies have also shown an association between PD‐L1 expression and the prognosis of patients with thymic epithelial tumors (TETs). In this study, we systematically evaluated the prognostic and clinicopathological roles of PD‐L1 expression in TETs. Methods We searched the literature through PubMed, Embase and Cochrane library and chose the eligible studies, and subsequently performed a meta‐analysis to evaluate the prognostic and clinicopathological roles of PD‐L1 expression in TETs. Results Six of the 75 articles found in the literature were selected. PD‐L1 expression was significantly related to unfavorable overall survival (hazard ratio 1.52, 95% confidence interval [CI]: 1.01–2.30, P = 0.046) in TETs. PD‐L1 expression was significantly associated with male gender (odds ratio [OR] 1.55, 95% CI: 1.08–2.22, P = 0.017) and higher Masaoka stage (OR 3.93, 95% CI: 2.44–6.32, P < 0.001). Conclusions PD‐L1 expression was correlated with unfavorable prognosis in TETs, indicating PD‐L1 expression could help determine the prognosis of TET patients.

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“…Therefore, tumors with high TMB are more sensitive to immunotherapy. In recent years, programmed cell death-1 (PD-1)/ programmed death-ligand 1 (PD-L1) checkpoint inhibitors therapy has opened a new chapter in the treatment of advanced TETs [9][10][11]. However, Rajan et al [12] reported that, in patients with relapsed thymoma, PD-L1 inhibition has anti-tumor activity but this is accompanied by a high frequency of immune-related adverse events.…”

Section: Introductionmentioning

confidence: 99%

Prognostic analysis of tumor mutation burden combined with immune infiltration of Thymic epithelial tumors

Ruan¹,

Liú²,

Wang³

et al. 2020

Preprint

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Background: Thymic epithelial tumors (TETs) are uncommon neoplasms with poor prognosis and limited effective therapeutic options. This study aims to investigate the prognosis of tumor mutation burden (TMB) and the potential association with immune infiltrates in TETs. Methods: Tumor mutation burden (TMB) was calculated using Maftools package and the samples were classified into high-TMB and low- TMB groups. Differentially expressed genes (DEGs) combined with immune cell infiltration and survival rate were analyzed between the low-TMB and high-TMB groups.Results: Single nucleotide polymorphism (SNP) occurred more frequently than insertion or deletion, and C>T was the most common single nucleotide variants (SNV) in TETs. The results of Kaplan–Meier curve indicated that a high TMB was associated with worse clinical outcomes of TETs. Moreover, 3 hub immune genes associated with immune infiltration were significantly associated with prognosis. Besides, the TMB-related signature (TMBRS) model based on the three hub immune genes possessed good predictive value with area under curve (AUC) 0.729, and patients with higher TMBRS scores showed worse TETs outcomes. In addition, infiltration levels of native CD4+ T cell, activated memory CD4+ T cell and follicular helper T cells in low-TMB group were higher than those in high-TMB group, which were correlated positively with prognosis of TETs. Conclusion: TETs patients with low TMB have better prognosis than those with high TMB, and TMB might affect the development of TETs by regulating immune infiltration.

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Expression Patterns, Prognostic Value, and Intratumoral Heterogeneity of PD-L1 and PD-1 in Thymoma and Thymic Carcinoma

Abstract: This study confirms high expression of PD-L1 and PD-1 in TET and shows for the first time intratumoral heterogeneity of PD-L1 and PD-1 in thymoma patients.

Cited by 48 publications

References 56 publications

Immunotherapeutic potential of CD4 and CD8 single-positive T cells in thymic epithelial tumors

Immunotherapeutic potential of CD4 and CD8 single-positive T cells in thymic epithelial tumors

Prognostic and clinicopathological roles of programmed death‐ligand 1 (PD‐L1) expression in thymic epithelial tumors: A meta‐analysis

Prognostic analysis of tumor mutation burden combined with immune infiltration of Thymic epithelial tumors

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Expression Patterns, Prognostic Value, and Intratumoral Heterogeneity of PD-L1 and PD-1 in Thymoma and Thymic Carcinoma

Abstract: This study confirms high expression of PD-L1 and PD-1 in TET and shows for the first time intratumoral heterogeneity of PD-L1 and PD-1 in thymoma patients.

Cited by 48 publications

References 56 publications

Immunotherapeutic potential of CD4 and CD8 single-positive T cells in thymic epithelial tumors

Immunotherapeutic potential of CD4 and CD8 single-positive T cells in thymic epithelial tumors

Prognostic and clinicopathological roles of programmed death‐ligand 1 (PD‐L1) expression in thymic epithelial tumors: A meta‐analysis

­­Prognostic analysis of tumor mutation burden combined with immune infiltration of Thymic epithelial tumors

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Prognostic analysis of tumor mutation burden combined with immune infiltration of Thymic epithelial tumors