Clinical relevance and prognostic significance of PD-1/PD-Ls in non-metastatic bladder cancer: A role for PD-L2

Ariafar, Ali; Ghaedi, Meisam; Rezaeifard, Somayeh; Shahriari, Shadab; Zeighami, Shahryar; Ghaderi, Abbas; Faghih, Zahra

doi:10.1016/j.molimm.2020.05.010

Cited by 14 publications

(3 citation statements)

References 29 publications

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“…But, following tumor progression and escape, the frequency of these cells is severely reduced or their function is suppressed through expression of inhibitory immune checkpoint molecules (i.e. PD-1/PD-Ls and Tim3) as we observed in our previous [19] and recent studies (unpublished data). It should be also noted that T lymphocytes are heterogeneous populations with very different effector functions, both protumorigenic [FOXP + regulatory T (Treg) and type 2 helper T (Th2)] and antitumorigenic (CD8 + cytotoxic T and Th1).…”

Section: Discussionsupporting

confidence: 64%

Prognostic significance of immunoscore related markers in bladder cancer

et al. 2022

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Background The significance of total and specific subpopulations of tumor-infiltrating lymphocytes (TILs) in cancer is now well-documented. In the present study, we investigated the relevance of CD3+, CD8 +, CD45RO +, and FOXP3 + TILs to the prognosis and survival of patients with bladder cancer and the disease's clinical-pathological parameters. Methods Infiltration of each subset was immunohistochemically evaluated in both stromal and intratumoral regions of tumor tissues from 85 patients with urothelial cell carcinoma of the bladder, with known survival. Results Our results indicated that intratumoral CD45RO+ lymphocytes were significantly higher in high-grade tumors than in low-grade ones (P = 0.028). The frequencies of intratumoral CD3+ (P = 0.002), CD8 + (P = 0.008), intratumoral (P = 0.002), and stromal (P = 0.017) CD45RO+ lymphocytes were also higher in patients with muscular invasion than those without invasion. The frequencies of intratumoral CD3+ (P = 0.043), CD8+ (P = 0.003), CD45RO+ (P = 0.023), and total CD45RO+ (P = 0.015), showed variation in patients with different T-stage, as well; mostly increased in T2 versus Ta and T1. Comparing patients in different stages revealed an increase in the frequencies of total CD3+ (P = 0.011), intratumoral CD3+ (P = 0.006), total CD8+ (P = 0.012), intratumoral CD8+ (P = 0.009) and stromal CD8+ (P = 0.034), as well as total and stromal CD45RO+ lymphocytes (P = 0.01 and P = 0.034, respectively) in stage II comparing to stage I, while the frequencies of stromal CD3+ (P = 0.077) and CD8+ (P = 0.053) cells tended to be decreased in stage III compared to stage II. Conclusions We collectively observed that the frequency of immune cells, especially CD45RO+, CD3+, and CD8+ lymphocytes, were significantly higher in early-progressed tumors. This observation could be explained by continuous and prolonged stimulation of immune cells with tumor antigens during tumor progression or an increase in the recruiting factors, especially in the early stages, to eliminate tumor cells. However, with tumor progression to the late stages, the inhibitory microenvironment provided by tumor cells suppresses or changes the functionality of the effector and memory immune cells to help tumor growth. However, more functional studies with larger sample sizes are needed to reveal the real status of the immune system in patients with bladder cancer.

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Section: Discussionsupporting

confidence: 64%

Prognostic significance of immunoscore related markers in bladder cancer

et al. 2022

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“…Moreover, PD-L2 protein is expressed to varying degrees in stromal, endothelial, and tumor cells. Ariafar et al ( 47 ) found that PD-L2 expression on immune cells, especially in draining lymph nodes was valuable for predicting prognosis and survival, while PD-L2 expression on tumor cells was not associated with prognosis. Therefore, it is necessary to explore the function and prognostic value of PD-L2 at a cellular level.…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer analysis identifies PD-L2 as a tumor promotor in the tumor microenvironment

Jiang

Yuan

et al. 2023

Front. Immunol.

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BackgroundProgrammed cell death protein 1 (PD-1) receptor has two ligands,programmed death-ligand 1 (PD-L1) and PD-L2. When compared with PD-L1, PD-L2 has not received much attention, and its role remains unclear.MethodsThe expression profiles of pdcd1lg2 (PD-L2-encoding gene) mRNA and PD-L2 protein were analyzed using TCGA, ICGC, and HPA databases. Kaplan-Meier and Cox regression analyses were used to assess the prognostic significance of PD-L2. We used GSEA, Spearman’s correlation analysis and PPI network to explore the biological functions of PD-L2. PD-L2-associated immune cell infiltration was evaluated using the ESTIMATE algorithm and TIMER 2.0. The expressions of PD-L2 in tumor-associated macrophages (TAMs) in human colon cancer samples, and in mice in an immunocompetent syngeneic setting were verified using scRNA-seq datasets, multiplex immunofluorescence staining, and flow cytometry. After fluorescence-activated cell sorting, flow cytometry and qRT-PCR and transwell and colony formation assays were used to evaluate the phenotype and functions of PD-L2+TAMs. Immune checkpoint inhibitors (ICIs) therapy prediction analysis was performed using TIDE and TISMO. Last, a series of targeted small-molecule drugs with promising therapeutic effects were predicted using the GSCA platform.ResultsPD-L2 was expressed in all the common human cancer types and deteriorated outcomes in multiple cancers. PPI network and Spearman’s correlation analysis revealed that PD-L2 was closely associated with many immune molecules. Moreover, both GSEA results of KEGG pathways and GSEA results for Reactome analysis indicated that PD-L2 expression played an important role in cancer immune response. Further analysis showed that PD-L2 expression was strongly associated with the infiltration of immune cells in tumor tissue in almost all cancer types, among which macrophages were the most positively associated with PD-L2 in colon cancer. According to the results mentioned above, we verified the expression of PD-L2 in TAMs in colon cancer and found that PD-L2+TAMs population was not static. Additionally, PD-L2+TAMs exhibited protumor M2 phenotype and increased the migration, invasion, and proliferative capacity of colon cancer cells. Furthermore, PD-L2 had a substantial predictive value for ICIs therapy cohorts.ConclusionPD-L2 in the TME, especially expressed on TAMs, could be applied as a potential therapeutic target.

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“…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 ). SIGLEC15 is an emerging broad-spectrum target for normalization cancer immunotherapy and is complementary to PD-L1 ( Wang et al, 2019 ).…”

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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Clinical relevance and prognostic significance of PD-1/PD-Ls in non-metastatic bladder cancer: A role for PD-L2

Cited by 14 publications

References 29 publications

Prognostic significance of immunoscore related markers in bladder cancer

Prognostic significance of immunoscore related markers in bladder cancer

Pan-cancer analysis identifies PD-L2 as a tumor promotor in the tumor microenvironment

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

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