PD-L2 Is Constitutively Expressed in Normal and Malignant Urothelium

Dowell, Alexander C.; Munford, Haydn; Goel, Ankit; Gordon, Naheema S.; James, Nicholas D.; Cheng, Kar Keung; Ward, Douglas G.; Bryan, Richard T.

doi:10.3389/fonc.2021.626748

Cited by 14 publications

(9 citation statements)

References 31 publications

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“…Nevertheless, the prognostic significance of PD-L2 expression status in bladder cancer remains uncertain. Although earlier research suggested that PD-L2 human tumors are generally an independent predictor of responsiveness to PD-1 blockage (Dowell et al, 2021), other studies observed contrasting results. PD-L2 overexpression was not associated with a favorable prognosis regarding relapse or progression of non-muscle-invasive bladder cancer (NMIBC) or recurrence-free survival of MIBC (Le Goux et al, 2017).…”

Section: Discussionmentioning

confidence: 88%

Prognostic Significance of PD-L2 Expression in Association with Neutrophil-to-Lymphocyte Ratio in Urothelial Carcinoma of the Bladder

Hendri,

Soerohardjo,

Heriyanto

et al. 2023

Asian Pac J Cancer Prev

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Background: The prognostic significance of tumoral programmed death-ligand 2 ( PD-L2 ) expression in urothelial bladder cancer (UBCs) is under-investigated , although it can potentially to become a regulatory agent of cancer immunity. In the search for supporting biomarkers, the neutrophil-to-lymphocyte ratio (NLR) as a readily available surrogate marker of immune status has been associated with clinical outcomes and other prognostic factors in various types of cancer. Here we evaluate the prognostic ability of baseline NLR in addition to PD-L2 expression in bladder cancer. Methods: We used a retrospective cohort of UBCs patients from the authors’ institutions. We classified patients according to their PD-L2 and NLR levels. We associated the prognostic outcome of each group with disease-free survival (DFS) and overall survival (OS). Results: Thirty patients had a tumor with positive PD-L2 expression. We found no significant correlation between PD-L2 expression and NLR. PD-L2 status failed to provide a significant prognostic impact (disease-free survival [DFS] and overall survival [OS] rate at 5 years, 42.85% in PD-L2 -high versus 65.75% in PD-L2 -low patients; p = 0.057, 42.85% in PD-L2 -high patients versus 62.5% in PD-L2 -low patients; p = 0.112, respectively). NLR status also failed to exhibit a significant prognostic impact (DFS and OS rate at 5 years, 44.44% in PD-L2 -high versus 66.66% in PD-L2 -low patients; p = 0.232, 55.55% in PD-L2 -high versus 71.43% in PD-L2 -low patients; P = 0.894, respectively). When PD-L2 status and NLR status were combined, the NLR-low and PD-L2 -low were significant factors to predict a favorable disease-free survival (hazard ratio, 4.525 [95% confidence interval, 1.020 to 20.080]; P = 0.047. However, the multivariate analysis failed to show it as an independent factor. Conclusion: These findings suggest that the prognostic impact of PD-L2 expression could be affected by the NLR status.

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Section: Discussionmentioning

confidence: 88%

Prognostic Significance of PD-L2 Expression in Association with Neutrophil-to-Lymphocyte Ratio in Urothelial Carcinoma of the Bladder

Hendri,

Soerohardjo,

Heriyanto

et al. 2023

Asian Pac J Cancer Prev

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“…Thus, PD-1 blockade could harm protective autoimmunity and lead to different types of irAEs via activated lymphocytes ( 15 ). The urinary bladder is immune-privileged because a number of chemicals, toxins and antigens constantly exposed to this site, therefore, it is essential to maintain the integrity and tolerance of the urothelium ( 16 ). The pathological features of a nivolumab-induced cystitis have shown epithelial desquamation and interstitial oedema ( 9 ).…”

Section: Discussion and Review Of The Literaturementioning

confidence: 99%

“…As to the PD-1 blockade will prevent the interaction of PD-1 and its known ligands PD-L1 as well as PD-L2 ( 3 ). PD-L2 is constitutively expressed by normal urothelium in healthy individuals and those with urothelial bladder cancer, suggesting a potential role in maintaining tolerance ( 16 ), whether PD-1/PD-L2 also participates in the autoimmune course is worthy to be explored.…”

Section: Discussion and Review Of The Literaturementioning

confidence: 99%

Case Report: A Case of Sintilimab-Induced Cystitis/Ureteritis and Review of Sintilimab-Related Adverse Events

Yuan

Tang

et al. 2021

Front. Oncol.

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Immune checkpoint inhibitors (ICIs) have been proven to be beneficial in multiple advanced malignancies. However, the widespread use of ICIs also occurred with various immune-related adverse events (irAEs). Here, we first report a case of sintilimab-related cystitis/ureteritis. A 53-year-old man with driver gene-negative pulmonary adenocarcinoma (cT1cN3M1c, Stage IVB) was being treated with sintilimab in combination of paclitaxel-albumin and bevacizumab as second-line treatment. He was hospitalized for haematuria, pollakiuria, painful micturition and low back pain after three courses. Urinalysis showed red blood cells (RBCs) and white blood cells (WBCs) were obviously increased, and serum creatinine (sCr) level was also significantly elevated. Urine culture and cytology were both negative, and cystoscopy revealed diffused redness of bladder mucosa. Urinary ultrasonography showed mild hydronephrosis and dilated ureter. The patient was diagnosed as immunotherapy-related cystitis/ureteritis after a multidisciplinary team (MDT) meeting. Once the diagnosis was made, corticosteroid therapy was given, which rapidly resolved the patient’s symptoms and signs. Computer tomography angiography (CTA) and CT urography (CTU) was conducted after sCr level was back to normal and demonstrated ureter dilation and hydroureter. Once symptoms relieved, bladder biopsy was performed and confirmed the bladder inflammation. The patient was subsequently switched to maintenance dose of methylprednisolone and tapered gradually. Since sintilimab has been used in advanced malignancies, we first reported a rare case of sintilimab-induced cystitis/ureteritis and summarized sintilimab-related adverse events to improve the assessment and management of irAEs.

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“…Ipilimumab (IgG1 mAb) is an approved ICI drug of the anti-CTLA4 antibody to be used as a treatment of advanced melanoma and has demonstrated a significant and long-lasting effect in approximately 15 to 20% of treated patients ( Schadendorf et al, 2015 ). PD-L2, similar to PD-L1, is another ligand of PD-1, that has a prominent role in maintaining self-tolerance under normal physiological conditions, limiting T cell activation and proliferation in peripheral tissues ( Dowell et al, 2021 ). Previous studies have demonstrated that multiple tumor patients with PD-L2 expression had worse outcomes, even in the absence of PD-L1, including BCa ( Gao et al, 2009 ; Ariafar et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel Assessment Model Based on Molecular Subtypes of Hypoxia-Related LncRNAs for Prognosis of Bladder Cancer

Chen

Zhang

Wang

et al. 2021

Front. Cell Dev. Biol.

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Hypoxia is a common feature in various tumors that regulates aggressiveness. Previous studies have demonstrated that some dysregulated long non-coding RNAs (lncRNAs) are correlated with tumor progression, including bladder cancer (BCa). However, the prognostic effect of hypoxia-related lncRNAs (HRLs) and their clinical relevance, as well as their regulatory effect on the tumor immune microenvironment, are largely unknown in BCa. A co-expression analysis between hypoxia genes and lncRNA expression, which was downloaded from the TCGA database, was performed to identify HRLs. Univariate Cox regression analysis was performed to select the most desirable lncRNAs for molecular subtype, and further LASSO analysis was performed to develop a prognostic model. This molecular subtype based on four HRLs (AC104653, AL136084, AL139393, and LINC00892) showed good performance in the tumor microenvironment and tumor mutation burden. The prognostic risk model suggested better performance in predicting BCa patients’ prognosis and obtained a close correlation with clinicopathologic features. Furthermore, four of five first-line clinical chemotherapies showed different sensitivities to this model, and nine immune checkpoints showed different expression in the molecular subtypes or the risk model. In conclusion, this study indicates that this molecular subtype and risk model based on HRLs may be useful in improving the prognostic prediction of BCa patients with different clinical situations and may help to find a useful target for tumor therapy.

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PD-L2 Is Constitutively Expressed in Normal and Malignant Urothelium

Cited by 14 publications

References 31 publications

Prognostic Significance of PD-L2 Expression in Association with Neutrophil-to-Lymphocyte Ratio in Urothelial Carcinoma of the Bladder

Prognostic Significance of PD-L2 Expression in Association with Neutrophil-to-Lymphocyte Ratio in Urothelial Carcinoma of the Bladder

Case Report: A Case of Sintilimab-Induced Cystitis/Ureteritis and Review of Sintilimab-Related Adverse Events

A Novel Assessment Model Based on Molecular Subtypes of Hypoxia-Related LncRNAs for Prognosis of Bladder Cancer

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