Prognostic value of PD-1 and PD-L1 expression in patients with metastatic clear cell renal cell carcinoma

Ueda, Kousuke; Suekane, Shigetaka; Kurose, Hirofumi; Chikui, Katsuaki; Nakiri, Makoto; Nishihara, Kiyoaki; Matsuo, Mitsuyoshi; Kawahara, Akihiko; Yano, Hirohisa; Igawa, Tsukasa

doi:10.1016/j.urolonc.2018.07.003

Cited by 60 publications

(49 citation statements)

References 35 publications

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“…Clinical studies evaluating the efficacy of immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have proposed different potential markers such as tumorintrinsic immune checkpoint expression, the intensity of intratumoral CD8 + T cell infiltrates, or an enhanced interferon-γ signature to be predictive for therapy response. [31][32][33][34][35] Currently, immunohistochemically determined receptor status is the only widely used biomarker Open access prior immune checkpoint inhibition. However, the use of PD-L1 IHC as a predictive biomarker is confounded by multiple difficulties, such as the usage of different antibodies and expression scores, as well as interlaboratory and interobserver variability.…”

Section: Open Accessmentioning

confidence: 99%

LAG3(LAG-3,CD223) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma

Klümper

Ralser

Bawden

et al. 2020

J Immunother Cancer

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BackgroundLymphocyte activating 3 (LAG3, LAG-3, CD223) is a promising target for immune checkpoint inhibition in clear cell renal cell carcinoma (KIRC). The aim of this study was to investigate the epigenetic regulation ofLAG3in KIRC by methylation.MethodsWe correlated quantitativeLAG3methylation levels with transcriptional activity, immune cell infiltration, and overall survival in a cohort of n=533 patients with KIRC and n=160 normal adjacent tissue (NAT) samples obtained from The Cancer Genome Atlas (TCGA). Furthermore, we analyzedLAG3methylation in peripheral blood mononuclear cells (PBMCs) and KIRC cell lines. We validated correlations between LAG3 expression, immune cell infiltrates, survival, and methylation in an independent KIRC cohort (University Hospital Bonn (UHB) cohort, n=118) by means of immunohistochemistry and quantitative methylation-specific PCR.ResultsWe found differential methylation profiles among PBMCs, NAT, KIRC cell lines, and KIRC tumor tissue. Methylation strongly correlated with LAG3 mRNA expression in KIRCs (TCGA cohort) and KIRC cell lines. In the UHB cohort, methylation correlated with LAG3-positive immune cells and tumor-intrinsic LAG3 protein expression. Furthermore,LAG3methylation strongly correlated with signatures of distinct immune cell infiltrates, an interferon-y signature (TCGA cohort), and immunohistochemically quantified CD45+, CD8+, and CD4+immune cell infiltrates (UHB cohort). LAG3 mRNA expression (TCGA cohort), methylation (both cohorts), and tumor cell-intrinsic protein expression (UHB cohort) was significantly associated with overall survival.ConclusionOur data suggest an epigenetic regulation of LAG3 expression in tumor and immune cells via DNA methylation. LAG3 expression and methylation is associated with a subset of KIRCs showing a distinct clinical course and immunogenicity. Our study provides rationale for further testingLAG3DNA methylation as a predictive biomarker for response to LAG3 immune checkpoint inhibitors.

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Section: Open Accessmentioning

confidence: 99%

LAG3(LAG-3,CD223) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma

Klümper

Ralser

Bawden

et al. 2020

J Immunother Cancer

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“…The prognosis of advanced RCC is poor in part because RCC is often resistant to traditional therapies such as radiation therapy and chemotherapy. Epidermal growth factor receptor‐tyrosine kinase inhibitors and immunocheckpoint inhibitors targeting PD‐1 or its ligand PD‐L1 showed promising therapeutic efficacy in advanced RCC . Recent reports showed that the expression of EGFR and PD‐L1 is a poor prognostic factor in RCC .…”

Section: Introductionmentioning

confidence: 99%

“…Epidermal growth factor receptor‐tyrosine kinase inhibitors and immunocheckpoint inhibitors targeting PD‐1 or its ligand PD‐L1 showed promising therapeutic efficacy in advanced RCC . Recent reports showed that the expression of EGFR and PD‐L1 is a poor prognostic factor in RCC . Prognostic biomarkers are important in the guidance of therapeutic options and surveillance strategies .…”

Section: Introductionmentioning

confidence: 99%

Claspin overexpression is associated with high‐grade histology and poor prognosis in renal cell carcinoma

et al. 2020

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Renal cell carcinoma (RCC) is one of the most common human cancers. We previously reported that claspin is a key regulator in the progression of gastric cancer, and it likely plays an important role in cancer stem cells of gastric cancer. However, the significance of claspin in RCC has not been examined. First, we analyzed the expression and distribution of claspin in 95 RCC cases by immunohistochemistry. In the nonneoplastic kidney, the staining of claspin was either weak or absent, whereas RCC tissue showed nuclear staining. In total, claspin expression was detected in 45 (47%) of 95 RCC cases. The claspin staining appeared relatively stronger in high nuclear grade RCC than in low nuclear grade RCC. Claspin‐positive RCC cases were associated with higher T grade, tumor stage, nuclear grade, vein invasion, and poorer prognosis. CLSPN siRNA treatment decreased RCC cell proliferation. The levels of phosphorylated Erk and Akt were lower in CLSPN siRNA‐transfected RCC cells than in control cells. In addition, claspin was coexpressed with CD44, epidermal growth factor receptor, p53, and programmed death ligand‐1. These results suggest that claspin plays an important role in tumor progression in RCC and might be a prognostic marker and novel therapeutic target molecule.

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“…Several recent studies and meta-analyses have shown that PD-L1 expression correlates with clinical-pathological prognostic factors in RCC, such as the WHO/ISUP grade, presence of necrosis and sarcomatoid features, tumor size, and TNM stage [140,141].…”

Section: Inflammation As Prognostic Factormentioning

confidence: 99%

“…Hara et al also showed that positive expression of immune-checkpoint-associated molecules, including PD-1, PD-L1, and PD-L2, is related to poor outcomes in metastatic RCC patients who received TKIs as first-line systemic therapy [140]. A retrospective study by Ueda et al reported that PD-1 expression is not only a prognostic indicator for poor OS in patients with metastatic RCC receiving molecular targeted therapies [141].…”

Section: Inflammation As Predictive Factormentioning

confidence: 99%

The Interplay between Inflammation, Anti-Angiogenic Agents, and Immune Checkpoint Inhibitors: Perspectives for Renal Cell Cancer Treatment

Brighi

Farolfi

Conteduca

et al. 2019

Cancers

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Treatment options for metastatic renal cell carcinoma (RCC) have been expanding in the last years, from the consolidation of several anti-angiogenic agents to the approval of immune checkpoint inhibitors (ICIs). The rationale for the use of immunomodulating agents derived from the observation that RCC usually shows a diffuse immune-cell infiltrate. ICIs target Cytotoxic T Lymphocytes Antigen 4 (CTLA-4), programmed death 1 (PD-1), or its ligand (PD-L1), showing promising therapeutic efficacy in RCC. PD-L1 expression is associated with poor prognosis; however, its predictive role remains debated. In fact, ICIs may be a valid option even for PD-L1 negative patients. The establishment of valid predictors of treatment response to available therapeutic options is advocated to identify those patients who could benefit from these agents. Both local and systemic inflammation contribute to tumorigenesis and development of cancer. The interplay of tumor-immune status and of cancer-related systemic inflammation is pivotal for ICI-treatment outcome, but there is an unmet need for a more precise characterization. To date, little is known on the role of inflammation markers on PD-1 blockade in RCC. In this paper, we review the current knowledge on the interplay between inflammation markers, PD-1 axis, and anti-angiogenic agents in RCC, focusing on biological rationale, implications for treatment, and possible future perspectives.

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Prognostic value of PD-1 and PD-L1 expression in patients with metastatic clear cell renal cell carcinoma

Abstract: PD-1 and PD-L1 expression is significantly associated with adverse clinicopathological features in CCRCC. Furthermore, PD-1 expression could be one of the biomarkers suggesting poor outcome in patients with metastatic CCRCC receiving molecular targeted therapies.

Cited by 60 publications

References 35 publications

LAG3(LAG-3,CD223) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma

LAG3(LAG-3,CD223) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma

Claspin overexpression is associated with high‐grade histology and poor prognosis in renal cell carcinoma

The Interplay between Inflammation, Anti-Angiogenic Agents, and Immune Checkpoint Inhibitors: Perspectives for Renal Cell Cancer Treatment

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