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CD161, a promising Immune Checkpoint, correlates with Patient Prognosis: A Pan-cancer Analysis.

ABSTRACT: Background: CD161 is a promising immune checkpoint mainly expressed on natural killer (NK) cells and is essential for immunoregulatory functions. However, it remains obscure how CD161 correlates with immune infiltration and patient prognosis in pan-cancer. Methods: We employed HPA, TCGA, GTEx, TIMER2.0, and GEPIA2 databases as well as R language to analyze and visualize CD161 in cancers. Our twenty-four glioma samples were sequenced for validation. Results: Overall, CD161 was differentially expressed between most paired cancer and normal controls. Higher CD161 expression was associated with poorer overall survival (OS) in the TCGA LGG (HR = 2.18, 95%CI = 1.79-2.66, P < 0.001) and UVM (HR = 1.32, 95%CI = 1.05-1.65, P = 0.016) cohorts. In these two cancer types, CD161 was significantly correlated with expression levels of recognized immune checkpoints and the abundance of markers of specific immune subsets, including CD8+ T cells, dendric cells (DCs), M2 macrophages, and exhausted T cells (Texs). In addition, CD161 was involved in several immune pathways in LGG and UVM, highlighting its role in regulating immune processes in the context of oncology. Conclusions: CD161 is a potential prognostic biomarker and immunotherapy target in human cancers, especially brain lower grade gliomas.

SUBMITTER: Ye W

PROVIDER: S-EPMC8489134 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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CD161, a promising Immune Checkpoint, correlates with Patient Prognosis: A Pan-cancer Analysis.

Ye Wenrui W Luo Cong C Li Chenglong C Liu Zhixiong Z Liu Fangkun F

Journal of Cancer 20210909 21

Background: CD161 is a promising immune checkpoint mainly expressed on natural killer (NK) cells and is essential for immunoregulatory functions. However, it remains obscure how CD161 correlates with immune infiltration and patient prognosis in pan-cancer. Methods: We employed HPA, TCGA, GTEx, TIMER2.0, and GEPIA2 databases as well as R language to analyze and visualize CD161 in cancers. Our twenty-four glioma samples were sequenced for validation. Results: Overall, CD161 wa ...[more]

PMID: 34659549

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Project description:BackgroundCD161, encoded by killer cell lectin-like receptor B1 gene, is a newly reported candidate inhibitor of tumour-infiltrating T cells. Antibody-mediated CD161 blockade enhances T cell-mediated killing of cancer cells in vitro and in vivo in several tumour types. We evaluated the role of CD161 using The Cancer Genome Atlas (TCGA) Pan-Cancer Data.MethodsCD161 expression was analysed using RNAseq data from TCGA and the Genotype-Tissue Expression (GTEx) database. HPA, GeneCards, and String database were used to explore the protein information of CD161. The prognostic value of CD161 was analysed using clinical survival data from the TCGA. Enrichment analysis of CD161 was conducted using the R package "clusterProfiler". We downloaded the immune cell infiltration score of TCGA samples from published articles and online databases and performed a correlation analysis between immune cell infiltration levels and CD161 expression. We further assessed the association between CD161 and immune checkpoints, immune activating genes, immunosuppressive genes, chemokines, and chemokine receptors.FindingsCD161 was differentially expressed and predicted better survival status in most tumour types in TCGA. In addition, CD161 expression was significantly associated with immunoregulatory interactions between lymphoid and non-lymphoid cells. CD161 expression was closely correlated with T cell infiltration, immune checkpoints, immune activating genes, immunosuppressive genes, chemokines, and chemokine receptors.InterpretationOur results suggest that CD161 is a potential cancer biomarker. CD161 might synergize with other immune checkpoints to regulate the immune microenvironment, which could be applied in the development of new-targeted drugs for immunotherapy.FundingThis work was supported by the National Nature Science Foundation of China (grant numbers 81773008, 81672756, 81872399, 81972897), the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2015), the Natural Science Foundation of Guangdong Province (grant number 2017A030311023), the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program: 2017BT01S131 and the Guangzhou Technology Project (grant number 201804010044), National Key R&D Program of China (Grant Nos. 2020YFC2006400), Key-Area Research and Development Program of Guangdong Province (2019B020227004).

Project description:BackgroundImmunotherapy has significantly improved patient outcomes, but encountered obstacles recently. CD96, a novel immune checkpoint expressed on T cells and natural killer (NK) cells, is essential for regulating immune functions. However, how CD96 correlating with immune infiltration and patient prognosis in pan-cancer remains unclear.MethodsHPA, TCGA, GEO, GTEx, Oncomine, TIMER2.0, PrognoScan, Linkedomics, Metascape, and GEPIA2 databases were used to analyze CD96 in cancers. Visualization of data was mostly achieved by R language, version 4.0.2.ResultsIn general, CD96 was differentially expressed between most cancer and adjacent normal tissues. CD96 significantly impacted the prognosis of diverse cancers. Especially, high CD96 expression was associated with poorer overall survival (OS) and disease-specific survival (DSS) in the TCGA lower grade glioma (LGG) cohort (OS, HR = 2.18, 95% CI = 1.79-2.66, P < 0.001). The opposite association was significantly observed in skin cutaneous melanoma (SKCM) cohort (OS, HR = 0.96, 95% CI = 0.94-0.98, P < 0.001). Notably, SKCM samples demonstrated the highest CD96 mutation frequency among all cancer types. Furthermore, in most cancers, CD96 expression level was significantly correlated with expression levels of recognized immune checkpoints and abundance of multiple immune infiltrates including CD8+ T cells, dendric cells (DCs), macrophages, monocytes, NK cells, neutrophils, regulatory T cells (Tregs), and follicular helper T cells (Tfh). CD96 was identified as a risk factor, protective factor, and irrelevant variable in LGG, SKCM and adrenocortical carcinoma (ACC), respectively. CD96 related genes were involved in negative regulation of leukocyte in LGG, however, involved in multiple positive immune processes in SKCM. Furthermore, CD96 was significantly associated with particular immune marker subsets. Importantly, it strongly correlated with markers of type 1 helper T cell (Th1) in SKCM, but not in LGG or ACC either.ConclusionsCD96 participates in diverse immune responses, governs immune cell infiltration, and impacts malignant properties of various cancer types, thus standing as a potential biomarker for determining patient prognosis and immune infiltration in multiple cancers, especially in glioma and melanoma.

Project description:BackgroundCD161, encoded by the killer cell lectin-like receptor B1 (KLRB1) gene, exhibits varied roles among different tumors. This study aimed to explore both the potential value of CD161 as a prognostic biomarker for hepatocellular carcinoma (HCC) and its association with immune cell infiltration.MethodsA total of 109 HCC patients who underwent surgery were retrospectively analyzed. Immunohistochemistry, bioinformatic analyses, and statistical measurements were used to investigate the associations between CD161 expression, immune cell infiltration, and clinical outcomes in both public databases and in-house cohorts.ResultsCD161 was highly expressed at both protein and mRNA levels in adjacent normal tissues compared to tumor tissues of HCC patients. Meanwhile, CD161 was enriched in HCC cases characterized by smaller tumor sizes (≤5 cm) and the absence of portal vein tumor thrombus. Individuals with high CD161 expression showed extended overall survival (OS) and relapse free survival (RFS) compared to those with lower CD161 levels. CD161 was identified as an independent prognostic indicator for both OS and RFS. In addition, the enrichment analysis indicated a close correlation between CD161 and immune response, as well as between CD161 and the signaling pathways of cytokines and chemokines, implying its role in immune regulation during cancer development. Specifically, CD161 expression was positively associated with immunomodulators and tumor-infiltrating immune cells, especially CD8+T cells, CD4+T cells, and dendritic cells. Multiple public databases showed that patients with high CD161 expression were more likely to derive benefits from immunotherapy.ConclusionCD161 was identified as a promising prognostic biomarker for HCC, as its expression indicates a favorable prognosis. Additionally, CD161 is closely linked to high infiltration of immune cells, participates in the regulation of the tumor immune microenvironment, and holds promise as a potential biomarker for predicting the efficacy of immunotherapy.

Project description:Background: The clinical implementation of immune-checkpoint inhibitors (ICIs) targeting CTLA4, PD-1, and PD-L1 has revolutionized the treatment of cancer. However, the majority of patients do not derive clinical benefit. Further development is needed to optimize the approach of ICI therapy. Immunotherapy combined with other forms of treatment is a rising strategy for boosting antitumor responses. CD93 was found to sensitize tumors to immune-checkpoint blocker therapy after the blockade of its pathway. However, its role in immune and ICB therapy across pan-cancer has remained unexplored. Methods: In this study, we provide a comprehensive investigation of CD93 expression in a pan-cancer manner involving 33 cancer types. We evaluated the association of CD93 expression with prognosis, mismatch repair, tumor mutation burden, and microsatellite instability, immune checkpoints, tumor microenvironment, and immune using multiple online datasets, including The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, Genotype Tissue-Expression, cBioPortal, Tumor Immune Estimation Resource database, and Tumor Immune Single-cell Hub. Results: CD93 expression varied strongly among cancer types, and increased CD93 gene expression was associated with poor prognosis as well as higher immune factors in most cancer types. Additionally, the level of CD93 was significantly correlated with MMR, TMB, MSI, immune checkpoints, TME, and immune cell infiltration. Noticeably, our results mediated a strong positive contact between CD93 and CAFs, endothelial cells, myeloid dendritic cells, hematopoietic stem cells, mononuclear/macrophage subsets, and neutrophils while a negative correlation with Th1, MDSC, NK, and T-cell follicular helper in almost all cancers. Function analysis on CD93 revealed a link between itself and promoting cancers, inflammation, and angiogenesis. Conclusion: CD93 can function as a prognostic marker in various malignant tumors and is integral in TME and immune infiltration. Inhibition of the CD93 pathway may be a novel and promising strategy for immunotherapy in human cancer. Further explorations of the mechanisms of CD93 in the immune system may help improve cancer therapy methods.

Dataset Information

CD161, a promising Immune Checkpoint, correlates with Patient Prognosis: A Pan-cancer Analysis.

Publications

CD161, a promising Immune Checkpoint, correlates with Patient Prognosis: A Pan-cancer Analysis.

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