Programmed Death Ligand 1 Expression Among 700 Consecutive Endometrial Cancers: Strong Association With Mismatch Repair Protein Deficiency

Li, Zaibo; Joehlin‐Price, Amy; Rhoades, Jennifer; Ayoola-Adeola, Martins; Miller, Kurt W.; Parwani, Anil V.; Backes, Floor J.; Felix, Ashley S.; Suarez, Adrian A.

doi:10.1097/igc.0000000000001120

Cited by 42 publications

(50 citation statements)

References 35 publications

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“…The prognostic value of PD-L1 in EC has been explored in previous studies (9)(10)(11)(12)(13)(14)(15)(16)(17), but the results were conflicting. We systemically searched eligible studies covering this topic and meta-analyzed the data.…”

Section: Discussionmentioning

confidence: 99%

“…The total sample size was 1,615, with individual sample sizes ranging from 53 to 700. The included studies were from 7 countries, including 2 studies in the USA (11,15), 2 studies in Turkey (12,16), and one each in China (9), Korea (10), Egypt (13), Japan (14), and Greece (17). All eligible IHC methods were used to detect PD-L1 expression in cancer tissue and a retrospective study design was used.…”

Section: Characteristics Of Included Studiesmentioning

confidence: 99%

“…Eight studies enrolled patients with FIGO stages I-IV (10-17) and one study recruited patients with FIGO stages I-III (9). Four studies (10,14,16,17) provided data on the association between PD-L1 and OS, and four other studies (10,11,14,17) reported information on PFS. Seven studies (9-13, 15, 17) investigated the relationship between PD-L1 and clinical factors.…”

Section: Characteristics Of Included Studiesmentioning

confidence: 99%

“…The pooled data were as follows: Table 2). Regarding PFS, 4 included studies (10,11,14,17) presented relevant data. The combined results were HR = 1.12, 95% CI = 0.50-2.54, and p = 0.778 (Table 2; Figure 2B).…”

Section: Pd-l1 and Prognosismentioning

confidence: 99%

“…PD-L1 expression has been shown to be a prognostic marker of prognosis in various cancers, including lung cancer, esophageal squamous cell carcinoma, pancreatic cancer, and colorectal cancer (5)(6)(7)(8). Many studies have also explored the prognostic value of PD-L1 in EC, with conflicting results (9)(10)(11)(12)(13)(14)(15)(16)(17). Some investigators have reported that elevated PD-L1 expression is associated with shorter survival (16).…”

Section: Introductionmentioning

confidence: 99%

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Prognostic and Clinicopathological Role of PD-L1 in Endometrial Cancer: A Meta-Analysis

Lü¹,

Li²,

Luo³

et al. 2020

Front. Oncol.

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Background: A series of studies have explored the prognostic value of programmed death-ligand 1 (PD-L1) in patients with endometrial cancer (EC); however, the results are controversial. Therefore, this meta-analysis was performed to estimate the associations between PD-L1 expression and the prognosis and clinicopathological features of EC. Methods: A comprehensive literature search of PubMed, Web of Science, and Embase was conducted up until September 06, 2019. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) were computed using the random-effects model (REM) or fixed-effects model (FEM). Odds ratios (ORs) and 95% CIs were calculated to evaluate the relationship between PD-L1 and clinicopathological factors. Results: A total of 9 studies with 1,615 patients were included in the meta-analysis. The combined data showed that high expression of PD-L1 was not significantly correlated with OS (HR = 1.20, 95% CI = 0.41-3.52, p = 0.737) or PFS (HR = 1.12, 95% CI = 0.50-2.54, p = 0.778) in EC. In addition, PD-L1 expression was significantly associated with poor differentiation (OR = 2.82, 95% CI = 1.96-4.06, P < 0.001) and advanced stage (OR = 1.71, 95% CI = 1.12-2.60, p = 0.013). Conclusion: This meta-analysis suggests that PD-L1 expression is not associated with poor prognosis in patients with EC. However, PD-L1 expression is positively correlated with poor differentiation and advanced tumor stage in EC.

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Section: Discussionmentioning

confidence: 99%

Section: Characteristics Of Included Studiesmentioning

confidence: 99%

Section: Characteristics Of Included Studiesmentioning

confidence: 99%

Section: Pd-l1 and Prognosismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prognostic and Clinicopathological Role of PD-L1 in Endometrial Cancer: A Meta-Analysis

Lü¹,

Li²,

Luo³

et al. 2020

Front. Oncol.

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The association between the tumor immune microenvironments and clinical outcome in low‐grade, early‐stage endometrial cancer patients

López-Janeiro

Villalba-Esparza

Brizzi

et al. 2022

The Journal of Pathology

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Endometrial tumors show substantial heterogeneity in their immune microenvironment. This heterogeneity could be used to improve the accuracy of current outcome prediction tools. We assessed the immune microenvironment of 235 patients diagnosed with low-grade, early-stage endometrial cancer. Multiplex quantitative immunofluorescence was carried out to measure CD8, CD68, FOXP3, PD-1, and PD-L1 markers, as well as cytokeratin (CK), on tissue microarrays. Clustering results revealed five robust immune response patterns, each associated with specific immune populations, cell phenotypes, and cell spatial clustering. Most samples (69%) belonged to the immune-desert subtype, characterized by low immune cell densities. Tumor-infiltrating lymphocyte (TIL)-rich samples (4%) displayed high CD8 + T-cell infiltration, as well as a high percentage of CD8/PD-1 + cells. Immune-exclusion samples (19%) displayed the lowest CD8 + infiltration combined with high PD-L1 expression levels in CK + tumor cells. In addition, they demonstrated high tumor cell spatial clustering as well as increased spatial proximity of CD8 + /PD-1 + and CK/PD-L1 + cells. FOXP3 and macrophage-rich phenotypes (3% and 4% of total samples) displayed relatively high levels of FOXP3 + regulatory T-cells and CD68 + macrophages, respectively. These phenotypes correlated with clinical outcomes, with immune-exclusion tumors showing an association with tumor relapse. When compared with prediction models built using routine pathological variables, models optimized with immune variables showed increased outcome prediction capacity (AUC = 0.89 versus 0.78) and stratification potential. The improved prediction capacity was independent of mismatch repair protein status and adjuvant radiotherapy treatment. Further, immunofluorescence results could be partially recapitulated using single-marker immunohistochemistry (IHC) performed on whole tissue sections. TIL-rich tumors demonstrated increased CD8 + T-cells by IHC, while immune-exclusion tumors displayed a lack of CD8 + T-cells and frequent expression of PD-L1 in tumor cells. Our results demonstrate the capability of the immune microenvironment to improve standard prediction tools in low-grade, early-stage endometrial carcinomas.

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The immunologic tumor microenvironment in endometrioid endometrial cancer in the morphomolecular context: mutual correlations and prognostic impact depending on molecular alterations

Willvonseder

Stögbauer

Steiger

et al. 2020

Cancer Immunol Immunother

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Objective POLE-mutant, microsatellite-instable (MSI), p53-mutant and non-specific molecular profile (NSMP) are TCGA-defined molecular subgroups of endometrial cancer (EC). Hypothesizing that morphology and tumor immunology might differ depending on molecular background concerning composition and prognostic impact, we aimed to comprehensively interconnect morphologic, immunologic and molecular data. Methods TCGA-defined molecular groups were determined by immunohistochemistry and sequencing in n = 142 endometrioid EC. WHO-defined histopathological grading was performed. The immunologic microenvironment (iTME) was characterised by the quantification of intraepithelial and stromal populations of tumor-infiltrating lymphocytes (TIL: overall T-cells; T-Killer cells; regulatory T-cells (Treg)). Immunologic parameters were correlated with WHO-grading, TCGA-subgroups and prognosis. Results High density TIL were significantly more frequent in high-grade (G3) compared to low-grade (G1/2) EC in the whole cohort and in the subgroup of POLE-wildtype-/microsatellite-stable-EC. MSI was associated with high-level TIL-infiltration when taking into account the type of mismatch repair defect (MLH1/PMS2; MSH2/MSH6). Prognostic impact of biomarkers depended on molecular subgroups: In p53-mutant EC, Treg were independently prognostic, in NSMP, the unique independently prognostic biomarker was WHO-grading. Conclusions EC morphology and immunology differ depending on genetics. Our study delineated two molecularly distinct subgroups of immunogenic EC characterized by high-density TIL-infiltration: MSI EC and high-grade POLE-wildtype/microsatellite-stable-EC. Prognostic impact of TIL-populations relied on TCGA-subgroups indicating specific roles for TIL depending on molecular background. In NSMP, histopathological grading was the only prognostic biomarker demonstrating the relevance of WHO-grading in an era of molecular subtyping.

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Programmed Death Ligand 1 Expression Among 700 Consecutive Endometrial Cancers: Strong Association With Mismatch Repair Protein Deficiency

Abstract: PD-L1 is expressed in a significant proportion of EC and is associated with mismatch repair deficiency, potentially representing a mechanism of tumor immune evasion and a therapeutic target in EC.

Cited by 42 publications

References 35 publications

Prognostic and Clinicopathological Role of PD-L1 in Endometrial Cancer: A Meta-Analysis

Prognostic and Clinicopathological Role of PD-L1 in Endometrial Cancer: A Meta-Analysis

The association between the tumor immune microenvironments and clinical outcome in low‐grade, early‐stage endometrial cancer patients

The immunologic tumor microenvironment in endometrioid endometrial cancer in the morphomolecular context: mutual correlations and prognostic impact depending on molecular alterations

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