Prognostic value of programmed-death-1 receptor (PD-1) and its ligand 1 (PD-L1) in testicular germ cell tumors

Čierna, Zuzana; Mego, Michal; Miškovská, Věra; Macháleková, Katarína; Chovanec, Michal; Světlovská, Daniela; Hainova, Katarina; Rejleková, Katarína; Macak, Dusan; Špánik, S.; Ondruš, D; Kajo, Karol; Mardiak, Jozef; Babál, Pavel

doi:10.1093/annonc/mdv574

Cited by 136 publications

(124 citation statements)

References 24 publications

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“…Substantial stromal expression of PD-L1 was also reported, though not in direct comparison with corresponding malignant cells. The presence of PD-L1 expression by immunohistochemistry has been suggested as a prognostic marker in TGCT with a correlation between low PD-L1 expression and improved progression-free and overall survival to non-immunotherapy interventions (21). A previous bioinformatic investigation of TCGA suggested high PD-L1 and CD8A expression in 48% of TGCT samples (22).…”

Section: Discussionmentioning

confidence: 99%

Clinical Response of a Patient to Anti–PD-1 Immunotherapy and the Immune Landscape of Testicular Germ Cell Tumors

Shah

Ward

Bao

et al. 2016

Cancer Immunology Research

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Anti–Programed Death 1 (PD-1) is standard immunotherapy for multiple cancers and the expression of one of its ligands, PD-L1, has been described in germ cell tumors (GCTs). Neither the clinical activity of anti–PD-1 nor the incidence of an immunoresponsive tumor microenvironment has been described for GCTs. A patient initially diagnosed with melanoma via fine needle aspiration was treated with one dose of antibody to PD-1. A core needle biopsy was subsequently performed to acquire sufficient tissue for molecular analysis, which led to a change in diagnosis to metastatic embryonal carcinoma. The testicular GCT cohort of The Cancer Genome Atlas (TCGA) was analyzed using a T-cell gene signature associated with benefit from immunotherapy. Primary tumors (N = 134) were categorized as high (T cell–inflamed), medium, or low (non-T cell–inflamed) by their T-cell signature derived from RNAseq data. Anti-PD-1 induced decreases in serum markers and a 33% reduction in tumor volume. Gene expression revealed a T cell–inflamed tumor microenvironment in 47% of testicular GCTs, including seminoma (83%) and non-seminoma (17%) tumor subtypes. Expression of alpha-fetoprotein (AFP) RNA correlated with lack of the T-cell signature, with increasing AFP RNA inversely correlating with the inflamed signature and expression of interferon-γ–associated genes. These data suggest that GCTs can respond to anti–PD-1 and that gene expression profiling supports investigation of immunotherapy for treatment of GCTs.

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Section: Discussionmentioning

confidence: 99%

Clinical Response of a Patient to Anti–PD-1 Immunotherapy and the Immune Landscape of Testicular Germ Cell Tumors

Shah

Ward

Bao

et al. 2016

Cancer Immunology Research

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“…One hundred and thirty six patients (56.7%) in this study were also included in our previous report [23]. Patients with concurrent malignancy other than non-melanoma skin cancer in the previous 5 years were excluded.…”

Section: Methodsmentioning

confidence: 99%

Prognostic role of programmed-death ligand 1 (PD-L1) expressing tumor infiltrating lymphocytes in testicular germ cell tumors

et al. 2017

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PurposeTesticular germ cell tumors (TGCTs) are nearly universally curable malignancies. Nevertheless, standard cisplatin-based chemotherapy is not curative in a small subgroup of patients. Previously, we showed that PD-L1 overexpression is associated with worse prognosis in TGCTs, while tumor infiltrating lymphocytes (TILs) are prognostic in different types of cancer. This study aimed to evaluate the prognostic value of PD-1 and PD-L1 expressing TILs in TGCTs.ResultsPD-L1 positive TILs were found significantly more often in seminomas (95.9% of patients) and embryonal carcinomas (91.0%) compared to yolk sac tumors (60.0%), choriocarcinomas (54.5%) or teratomas (35.7%) (All p < 0.05). TGCTs patients with high infiltration of PD-L1 positive TILs (HS ≥ 160) had significantly better progression-free survival (HR = 0.17, 95% CI 0.09 – 0.31, p = 0.0006) and overall survival (HR = 0.08, 95% CI 0.04 – 0.16, p = 0.001) opposite to patients with lower expression of PD-L1 (HS < 150). PD-1 expressing TILs were not prognostic in TGCTs.Materials and MethodsSurgical specimens from 240 patients with primary TGCTs were included into this translational study. The PD-1 and PD-L1 expression on tumor and TILs were detected by immunohistochemistry using anti-PD-1 and anti-PD-L1 monoclonal antibody. Scoring was performed semiquantitatively by weighted histoscore (HS) method.ConclusionsThe prognostic value of PD-L1 expressing TILs in TGCTs was demonstrated for the first time.

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“…In addition, PD-L1 has a pivotal role in the conversion of naive T cells to regulatory T cells (Tregs) by inhibiting the Akt-mammalian target of rapamycin (mTOR) signalling8. The expression of PD-L1 has been correlated with poor clinical outcomes in several human cancers9101112. Given this background, a PD-1/PD-L1 pathway blockade by targeted-antibodies (against PD-1 or PD-L1) is a highly promising therapy and has elicited durable antitumor responses and long-term remission in recent clinical trials13.…”

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confidence: 99%

The clinicopathological and prognostic significance of PD-L1 expression in gastric cancer: a meta-analysis of 10 studies with 1,901 patients

Zhang

Dong

Liu

et al. 2016

Sci Rep

120

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The prognostic value of programmed death-ligand 1 (PD-L1) in gastric cancer (GC) remains controversial. To clarify this problem, we performed a meta-analysis of research studies identified in the PubMed, EMBASE and the Cochrane Library databases. A total of 1,901 patients in 10 studies were enrolled in this meta-analysis, and the pooled hazard ratio (HR) of 1.64 (95% CI 1.11 to 2.43; P = 0.01) indicated that PD-L1 expression is associated with a shorter overall survival (OS). The pooled odds ratios (ORs) indicated that PD-L1 expression was associated with tumour size (OR = 1.87, 95% CI 1.25 to 2.78; P = 0.002) and lymph node status (OR = 2.17, 95% CI 1.04 to 4.52; P = 0.04). However, PD-L1 had no correlation with gender, age, cancer location, differentiation, depth of invasion, and tumour stage. This meta-analysis indicates that PD-L1 expression is a valuable predictor of the prognosis of patients with GC. PD-L1 expression could be used for identifying a subgroup of patients, who would potentially benefit from targeted therapy against PD-1 or PD-L1. Well-designed large-cohort studies are needed to confirm these findings.

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Prognostic value of programmed-death-1 receptor (PD-1) and its ligand 1 (PD-L1) in testicular germ cell tumors

Abstract: In this translational study, we showed, for the first time, the prognostic value of PD-L1 expression in TGCTs and our data imply that the PD-1/PD-L1 pathway could be a novel therapeutic target in TGCTs.

Cited by 136 publications

References 24 publications

Clinical Response of a Patient to Anti–PD-1 Immunotherapy and the Immune Landscape of Testicular Germ Cell Tumors

Clinical Response of a Patient to Anti–PD-1 Immunotherapy and the Immune Landscape of Testicular Germ Cell Tumors

Prognostic role of programmed-death ligand 1 (PD-L1) expressing tumor infiltrating lymphocytes in testicular germ cell tumors

The clinicopathological and prognostic significance of PD-L1 expression in gastric cancer: a meta-analysis of 10 studies with 1,901 patients

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