PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

Obeid, Joseph M.; Erdag, Gulsun; Smolkin, Mark E.; Deacon, Donna H.; Patterson, James W.; Chen, Leiping; Bullock, Timothy N. J.; Slingluff, Craig L.

doi:10.1080/2162402x.2016.1235107

Cited by 107 publications

(111 citation statements)

References 70 publications

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“…Immune checkpoints commonly play significant roles in triggering the cancer immunity escape by mediating the interaction between tumor cells and TIICs, so their expressions were commonly positively correlated with TIICs abundance [32,33]. In our research, we found that the high infiltration of TIICs predicted worse outcomes in total LGG patients.…”

Section: Discussionsupporting

confidence: 50%

Characterization of clinical significance of PD-1/PD-Ls expression and methylation in patients with low grade glioma

Mei

Cai

et al. 2020

Preprint

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Background: Immune checkpoints play crucial roles in immune escape of cancer cells. However, the exact prognostic values of expression and methylation of programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1) and PD-L2 in low-grade glioma (LGG) have not been defined yet. Methods:A total of 514 LGG samples from TCGA dataset containing both PD-1, PD-L1 and PD-L2 expression, DNA methylation, and survival data were enrolled into our study. The clinical significance of PD-1/PD-Ls expression and methylation inLGG were explored. Besides, the correlation between PD-1/PD-Ls expression and methylation with the infiltration levels of tumor-infiltrating immune cells (TIICs) was assessed. Moreover, GO enticement analysis of PD-1/PD-Ls co-expressed genes was performed as well. R 3.6.2 and GraphPad Prism 8 were applied as main tools for the statistical analysis and graphical exhibition.Results: PD-1/PD-Ls had distinct co-expression patterns in LGG tissues. The expression and methylation status of PD-1/PD-Ls seemed to be various in differentLGG subtypes. Besides, upregulated PD-1/PD-Ls expression and hypo-methylation of PD-1/PD-Ls were associated with worse survival in LGG patients. In addition, PD-1/PD-Ls expression was revealed to be positively associated with TIICs infiltration, while their methylation was negatively associated with TIICs infiltration.Moreover, the PD-1/PDLs correlated gene profiles screening and Gene Ontology (GO) enrichment analysis uncovered that PD-1/PDLs and their positively correlated gene mainly participated in immune response related biological processes. Conclusions:High expression and hypo-methylation of PD-1/PD-Ls significantly correlated with unfavorable survival in LGG patients, suggesting LGG patients may benefit from PD1/PD-Ls checkpoint inhibitors treatment.

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Section: Discussionsupporting

confidence: 50%

Characterization of clinical significance of PD-1/PD-Ls expression and methylation in patients with low grade glioma

Mei

Cai

et al. 2020

Preprint

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“…1–4 Studies from our group and others indicate that the major mechanism driving melanoma tumor cell PD-L1 expression is an association with tumor-infiltrating lymphocytes (TIL), consistent with an endogenous antitumor immune response that may be unleashed with anti-PD-1/PD-L1 therapies. 5 Such adaptive PD-L1 expression by melanoma is not dependent on BRAF, NRAS, or c-KIT mutational status.…”

mentioning

confidence: 70%

Melanoma subtypes demonstrate distinct PD-L1 expression profiles

Kaunitz

Cottrell

Lilo

et al. 2017

Laboratory Investigation

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112

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PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-γ-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n = 16), mucosal (n = 36), uveal (n = 103), and chronic sun-damaged (CSD) (n = 45) melanomas (24 lentigo maligna, 13 ‘mixed’ desmoplastic, and 8 ‘pure’ desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P<0.0001). Compared to our previously characterized cohort of cutaneous melanomas, the proportion of PD-L1(+) tumors was lower in uveal (P = 0.0002) and higher in CSD (P = 0.0073) melanomas, while PD-L1 expression in the acral and mucosal subtypes was on par. PD-L1 expression in all subtypes correlated with a moderate–severe grade of CD8+ TIL (all, P<0.003), supporting an adaptive mechanism of expression induced during the host antitumor response. The tumor microenvironments observed in CSD melanomas segregated by whether they were the pure desmoplastic subtype, which showed lower levels of PD-L1 expression when compared to other CSD melanomas (P = 0.047). The presence of lymphoid aggregates was not associated with the level of PD-L1 expression, while PD-L1(+) cases with spindle cell morphology demonstrated higher levels of PD-L1 than those with a nested phenotype (P<0.0001). Our findings may underpin the reported clinical response rates for anti-PD-1 monotherapy, which vary by subtype.

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“…In fact, when whole transcriptome associations are performed, PDL2 is the gene most closely associated with PD-L1 expression in melanoma. 73 Not surprisingly, PD-L2 expression is also a positive prognostic feature in these patients, 73,74 likely because, similar to PD-L1, its expression in this tumor type tends to equate with an ongoing host response against tumor. The impact of PD-L2 expression as a predictive biomarker for anti-PD-1 blockade is not well understood at this time but is currently being explored by a number of investigative groups.…”

Section: Melanoma and Other Cutaneous Malignanciesmentioning

confidence: 95%

Implications of the tumor immune microenvironment for staging and therapeutics

et al. 2018

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Characterizing the tumor immune microenvironment enables the identification of new prognostic and predictive biomarkers, the development of novel therapeutic targets and strategies, and the possibility to guide first-line treatment algorithms. Although the driving elements within the tumor microenvironment of individual primary organ sites differ, many of the salient features remain the same. The presence of a robust antitumor milieu characterized by an abundance of CD8+ cytotoxic T-cells, Th1 helper cells, and associated cytokines often indicates a degree of tumor containment by the immune system and can even lead to tumor elimination. Some of these features have been combined into an ‘Immunoscore’, which has been shown to complement the prognostic ability of the current TNM staging for early stage colorectal carcinomas. Features of the immune microenvironment are also potential therapeutic targets, and immune checkpoint inhibitors targeting the PD-1/ PD-L1 axis are especially promising. FDA-approved indications for anti-PD-1/PD-L1 are rapidly expanding across numerous tumor types and, in certain cases, are accompanied by companion or complimentary PD-L1 immunohistochemical diagnostics. Pathologists have direct visual access to tumor tissue and in-depth knowledge of the histological variations between and within tumor types and thus are poised to drive forward our understanding of the tumor microenvironment. This review summarizes the key components of the tumor microenvironment, presents an overview of and the challenges with PD-L1 antibodies and assays, and addresses newer candidate biomarkers, such as CD8+ cell density and mutational load. Characteristics of the local immune contexture and current pathology-related practices for specific tumor types are also addressed. In the future, characterization of the host antitumor immune response using multiplexed and multimodality biomarkers may help predict which patients will respond to immune-based therapies.

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PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

Cited by 107 publications

References 70 publications

Characterization of clinical significance of PD-1/PD-Ls expression and methylation in patients with low grade glioma

Characterization of clinical significance of PD-1/PD-Ls expression and methylation in patients with low grade glioma

Melanoma subtypes demonstrate distinct PD-L1 expression profiles

Implications of the tumor immune microenvironment for staging and therapeutics

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