Expression of programmed death 1 (PD-1) and its ligand (PD-L1) in thymic epithelial tumors: Impact on treatment efficacy and alteration in expression after chemotherapy

Katsuya, Yuki; Horinouchi, Hidehito; Asao, Tetsuji; Kitahara, Shinsuke; Goto, Yasushi; Kanda, Shintaro; Fujiwara, Yutaka; Nokihara, Hiroshi; Yamamoto, Noboru; Watanabe, Shun‐ichi; Tsuta, Koji; Ohe, Yuichiro

doi:10.1016/j.lungcan.2016.05.007

Cited by 86 publications

(85 citation statements)

References 35 publications

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“…In the study of atezolizumab (Tecentriq ® , Hoffman-La Roche, Basel, Switzerland), an anti-PD-L1 antibody, IHC staining was assessed in tumor cells and tumor-infiltrating immune cells 23. However, many other studies have investigated staining intensity, incorporating the proportion of cells with positive expression for evaluation of PD-L1 expression 24,25. In addition, defining positivity, staining intensity, or cut-off values between low and high expression have differed among the previous studies.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of PD-L2 is associated with shorter relapse-free survival in patients with malignant salivary gland tumors

Chang¹,

Kim²,

Choi³

et al. 2017

OTT

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ObjectivesPD-1/PD-L1 and CTLA-4 have been investigated and are thought to play an important role in tumor evasion. This study aimed to investigate expression patterns of immune-related molecules, and their clinical impacts in malignant salivary gland tumors.Patients and methodsWe performed immunohistochemical staining for PD-L1, PD-L2, CTLA-4, PD-1, and CD8+ tumor-infiltrating lymphocytes in 70 malignant salivary gland tumors. Protein expression was assessed by H-score by multiplying the staining intensity by the percentage of cells with positive staining.ResultsThe tumors comprised mucoepidermoid carcinomas (38.6%), adenoid cystic carcinomas (21.4%), salivary duct carcinomas (15.7%), and others. In malignant salivary gland tumors, PD-L2 expression was high, while expression of PD-L1 was relatively low in terms of the percentage of positively stained cells and the staining intensity. In univariate analysis, PD-L2 expression (H-score <1 vs ≥1), PD-1 (H-score <1 vs ≥1), and CD8+ tumor-infiltrating lymphocytes (H-score <1 vs ≥1) were significant prognostic factors. In multivariate analysis, low PD-L2 expression (H-score <1) was independently associated with shorter relapse-free survival (hazard ratio =6.514; 95% confidence interval, 1.2–36.2; P=0.032).ConclusionIn summary, PD-L2 is potentially an important biomarker in malignant salivary gland tumors, especially in regard to relapse.

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Section: Discussionmentioning

confidence: 99%

Overexpression of PD-L2 is associated with shorter relapse-free survival in patients with malignant salivary gland tumors

Chang¹,

Kim²,

Choi³

et al. 2017

OTT

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“…An upregulation of PD-1 and/or PD-L1 after chemotherapy for leukemia, thymic epithelial tumors and ovarian cancer has been reported. [12][13][14][15] Identification of the effect of chemotherapy on the TME in MPM can guide the rational design of combination strategies of immune checkpoint inhibition with chemotherapeutics. [16][17][18] We investigated the expression of TIM-3 and LAG-3 in human MPM tumor tissue using immunohistochemistry (IHC), along with several other immune cell markers of the TME, and addressed their potential role as targets for immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma

et al. 2016

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Malignant pleural mesothelioma (MPM) is an aggressive cancer with a poor prognosis and an increasing incidence, for which novel therapeutic strategies are urgently required. Since the immune system has been described to play a presumed role in the protection against MPM, characterization of its tumor immune microenvironment (TME) and immune checkpoints can identify new immunotherapeutic targets and their predictive and/or prognostic value.To characterize the TME and the immune checkpoint expression profile, we performed immunohistochemistry (IHC) on formalin-fixed paraffin embedded (FFPE) tissue sections from 54 MPM patients (40 at time of diagnosis; 14 treated with chemotherapy). We stained for PD-1, PD-L1, TIM-3, LAG-3, CD4, CD8, CD45RO, granzyme B, FoxP3 and CD68. Furthermore, we analyzed the relationship between the immunological parameters and survival, as well as response to chemotherapy. We found that TIM-3, PD-1 and PD-L1 were expressed on both immune and tumor cells. Strikingly, PD-1 and PD-L1 expression on tumor cells was only seen in unpretreated samples. No LAG-3 expression was observed. CD45RO expression in the stroma was an independent negative predictive factor for response on chemotherapy, while CD4 and TIM-3 expression in lymphoid aggregates were independent prognostic factors for better outcome. Our data propose TIM-3 as a promising new target in mesothelioma. Chemotherapy influences the expression of immune checkpoints and therefore further research on the best combination treatment schedule is required.

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“…[1,10,11] Programed death 1 (PD-1) is a vital immune checkpoint receptor which is expressed on activated T cells. [12] Normally, the interaction between PD-1 and programed death ligand 1 (PD-L1) will lead to the inhibition of immune response, [13] thus preventing the excessive inflammation. Otherwise, PD-L1 was also found to be expressed in some tumor cells including those of NSCLC.…”

Section: Introductionmentioning

confidence: 99%

A meta-analysis of efficacy and safety of antibodies targeting PD-1/PD-L1 in treatment of advanced nonsmall cell lung cancer

Wang

2016

Medicine

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Background:Nonsmall cell lung cancer (NSCLC)-patients treated with standard chemotherapy experienced progression rapidly. A novel therapy based on programed death 1 (PD-1)/programed death ligand 1 (PD-L1) inhibitors showed an increasing potential in several malignancies including advanced NSCLC.Objectives:This article is a meta-analysis aiming to systematically evaluate the efficacy and safety profiles of PD-1/PD-L1 agents in patients with NSCLC.Data sources:Data were collected from eligible studies searched from PubMed, ScienceDirect, and Web of Science.Synthesis methods:Pooled hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) was estimated to assess the efficacy of PD-1/PD-L1 inhibitors versus docetaxel, pooled odds ratio (OR) was calculated for objective response rate (ORR). The overall frequency was estimated for 1-year OS, 1-year progression-free survival, and ORR. A subgroup analysis among NSCLC patients tested with different epidermal growth factor receptor (EGFR) status was also performed to figure out the relationship between EGFR status and efficacy of PD-1/PD-L1 therapies. OR for occurrence of any grade and grade 3 to 5 treatment-related adverse effect was calculated for evaluating the safety of PD-1/PD-L1 therapies.Results:Nine studies were included in this analysis. The pooled HRs for OS and PFS were 0.68 (95% confidence interval [CI] 0.61–0.75) and 0.83 (95% CI 0.75–0.91), respectively, the pooled OR for ORR was 1.83 (95% CI 1.41–2.36), indicating a significant improvement in OS, PFS, and ORR. In the results of subgroup analysis, the HR for OS in NSCLC patients was 1.05 (95% CI 0.69–1.59) in patients with mutant EGFR and 0.66 (95% CI 0.57–0.77) in patients with wild-type EGFR status. OR for occurrence was 0.36 (95% CI 0.28–0.46) in any grade treatment-related adverse effect and 0.18 (95% CI 0.14–0.22) in grade 3 to 5 treatment-related adverse effect, suggesting a superior safety profile of PD-1/PD-L1 inhibitors.Conclusion:The PD-1/PD-L1 therapy significantly prolonged the OS and improved the ORR, simultaneously lowering the treatment-related adverse effect events versus docetaxel.

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Expression of programmed death 1 (PD-1) and its ligand (PD-L1) in thymic epithelial tumors: Impact on treatment efficacy and alteration in expression after chemotherapy

Abstract: The substantially high expression of PD-L1 and the increase in PD-L1 and PD-1 expression after chemotherapy supports anti-PD-1/L1 drugs therapy for TM and TC as well as the development of a strategy for its sequential use after chemotherapy.

Cited by 86 publications

References 35 publications

Overexpression of PD-L2 is associated with shorter relapse-free survival in patients with malignant salivary gland tumors

Overexpression of PD-L2 is associated with shorter relapse-free survival in patients with malignant salivary gland tumors

Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma

A meta-analysis of efficacy and safety of antibodies targeting PD-1/PD-L1 in treatment of advanced nonsmall cell lung cancer

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