Dataset Information

The identification and functional analysis of CD8+PD-1+CD161+ T cells in hepatocellular carcinoma.

ABSTRACT: Immunotherapy is a powerful therapeutic strategy for end-stage hepatocellular carcinoma (HCC). It is well known that T cells, including CD8+PD-1+ T cells, play important roles involving tumor development. However, their underlying phenotypic and functional differences of T cell subsets remain unclear. We constructed single-cell immune contexture involving approximate 20,000,000 immune cells from 15 pairs of HCC tumor and non-tumor adjacent tissues and 10 blood samples (including five of HCCs and five of healthy controls) by mass cytometry. scRNA-seq and functional analysis were applied to explore the function of cells. Multi-color fluorescence staining and tissue micro-arrays were used to identify the pathological distribution of CD8+PD-1+CD161 +/- T cells and their potential clinical implication. The differential distribution of CD8+ T cells subgroups was identified in tumor and non-tumor adjacent tissues. The proportion of CD8+PD1+CD161+ T cells was significantly decreased in tumor tissues, whereas the ratio of CD8+PD1+CD161- T cells was much lower in non-tumor adjacent tissues. Diffusion analysis revealed the distinct evolutionary trajectory of CD8+PD1+CD161+ and CD8+PD1+CD161- T cells. scRNA-seq and functional study further revealed the stronger immune activity of CD8+PD1+CD161+ T cells independent of MHC class II molecules expression. Interestingly, a similar change in the ratio of CD8+CD161+/ CD8+CD161- T cells was also found in peripheral blood samples collected from HCC cases, indicating their potential usage clinically. We here identified different distribution, function, and trajectory of CD8+PD-1+CD161+ and CD8+PD-1+CD161- T cells in tumor lesions, which provided new insights for the heterogeneity of immune environment in HCCs and also shed light on the potential target for immunotherapy.

SUBMITTER: Li Z

PROVIDER: S-EPMC7599220 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The identification and functional analysis of CD8+PD-1+CD161+ T cells in hepatocellular carcinoma.

Li Zhixuan Z Zheng Bo B Qiu Xinyao X Wu Rui R Wu Tong T Yang Shuai S Zhu Yanjing Y Wu Xuan X Wang Shan S Gu Ziqi Z Shen Siyun S Wu Mengchao M Wang Hongyang H Chen Lei L

NPJ precision oncology 20201030

Immunotherapy is a powerful therapeutic strategy for end-stage hepatocellular carcinoma (HCC). It is well known that T cells, including CD8+PD-1+ T cells, play important roles involving tumor development. However, their underlying phenotypic and functional differences of T cell subsets remain unclear. We constructed single-cell immune contexture involving approximate 20,000,000 immune cells from 15 pairs of HCC tumor and non-tumor adjacent tissues and 10 blood samples (including five of HCCs and ...[more]

PMID: 33145436

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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: Aberrant activity of tyrosine-phosphorylated proteins is commonly associated with HCC metastasis. Cell signaling events driven by these proteins are implicated in numerous processes that alter cancer cell behavior. Exploring the activities and signaling pathways of these proteins in HCC metastasis may help in identifying new candidate molecules for HCC-targeted therapy. METHODS: Hep3B (a nonmetastatic HCC cell line) and MHCC97H (a highly metastatic HCC cell line) were used in this study, and the tyrosine-phosphorylated proteins expressed in these cell lines were profiled by a phosphoproteomics technique based on LC-MS/MS. Protein-protein interaction and functional clustering analyses were performed to determine the activities of the identified proteins and the signaling pathways closely related to HCC metastasis. RESULTS: In both cell lines, a total of 247 phosphotyrosine (pTyr) proteins containing 281 pTyr sites were identified without any stimulation. The involvement of almost 30% of these in liver or liver cancer has not been reported previously. Biological process clustering analysis indicated that pTyr proteins involved in cell motility, migration, protein autophosphorylation, cell-cell communication, and antiapoptosis functions were overexpressed during metastasis. Pathway clustering analysis revealed that signaling pathways such as those involved in EGFR signaling, cytokine- and chemokine-mediated signal transduction, and the PI3K and JAK-STAT cascades were significantly activated during HCC metastasis. Moreover, noncanonical regulation of the JNK cascade might also provide new targets for HCC metastasis. After comparing the pTyr proteins that were differentially expressed during HCC cell metastasis, we selected FER, a nonreceptor tyrosine kinase, and validated its role in terms of both expression and function. The data confirmed that FER might play a critical role in the invasion and metastasis of HCC. CONCLUSION: The identification of pTyr proteins and signaling pathways associated with HCC metastasis could provide useful information for selecting new molecular intervention targets. Moreover, FER might serve as a novel drug target in future HCC therapy.

Dataset Information

The identification and functional analysis of CD8+PD-1+CD161+ T cells in hepatocellular carcinoma.

Publications

The identification and functional analysis of CD8+PD-1+CD161+ T cells in hepatocellular carcinoma.

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