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  • 1
    Online-Ressource
    Online-Ressource
    Integrated Multi-Omics Landscape of Liver Metastases
    Elsevier BV ; 2023
    In:  Gastroenterology Vol. 164, No. 3 ( 2023-03), p. 407-423.e17
    Details
    In: Gastroenterology, Elsevier BV, Vol. 164, No. 3 ( 2023-03), p. 407-423.e17
    Materialart: Online-Ressource
    ISSN: 0016-5085
    URL: Article
    DOI: 10.1053/j.gastro.2022.11.029
    RVK:
    XA 44500
    Sprache: Englisch
    Verlag: Elsevier BV
    Publikationsdatum: 2023
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    Online-Ressource
    Online-Ressource
    M6A Demethylase ALKBH5 Regulates PD-L1 Expression and Tumor Immunoenvironment in Intrahepatic Cholangiocarcinoma
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 18 ( 2021-09-15), p. 4778-4793
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 18 ( 2021-09-15), p. 4778-4793
    Kurzfassung: N6-methyladenosine (m6A) has been reported as an important mechanism of posttranscriptional regulation. Programmed death-ligand 1 (PD-L1) is a primary immune inhibitory molecule expressed on tumor cells that promotes immune evasion. Here we report ALKBH5 as an important m6A demethylase that orchestrates PD-L1 expression in intrahepatic cholangiocarcinoma (ICC). Regulation of PD-L1 expression by ALKBH5 was confirmed in human ICC cell lines. Sequencing of the m6A methylome identified PD-L1 mRNA as a direct target of m6A modification whose levels were regulated by ALKBH5. Furthermore, ALKBH5 and PD-L1 mRNA were shown to interact. ALKBH5 deficiency enriched m6A modification in the 3′UTR region of PD-L1 mRNA, thereby promoting its degradation in a YTHDF2-dependent manner. In vitro and in vivo, tumor-intrinsic ALKBH5 inhibited the expansion and cytotoxicity of T cells by sustaining tumor cell PD-L1 expression. The ALKBH5-PD-L1–regulating axis was further confirmed in human ICC specimens. Single-cell mass cytometry analysis unveiled a complex role of ALKBH5 in the tumor immune microenvironment by promoting the expression of PD-L1 on monocytes/macrophages and decreasing the infiltration of myeloid-derived suppressor-like cells. Analysis of specimens from patients receiving anti-PD1 immunotherapy suggested that tumors with strong nuclear expression patterns of ALKBH5 are more sensitive to anti-PD1 immunotherapy. Collectively, these results describe a new regulatory mechanism of PD-L1 by mRNA epigenetic modification by ALKBH5 and the potential role of ALKBH5 in immunotherapy response, which might provide insights for cancer immunotherapies. Significance: This study identifies PD-L1 mRNA as a target of ALKBH5 and reveals a role for ALKBH5 in regulating the tumor immune microenvironment and immunotherapy efficacy.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-21-0468
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2021
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 3
    Online-Ressource
    Online-Ressource
    Trajectory and Functional Analysis of PD‐1 high CD4 + CD8 + T Cells in Hepatocellular Carcinoma by Single‐Cell Cytometry and Transcriptome Sequencing
    Wiley ; 2020
    In:  Advanced Science Vol. 7, No. 13 ( 2020-07)
    Details
    In: Advanced Science, Wiley, Vol. 7, No. 13 ( 2020-07)
    Kurzfassung: The spatial heterogeneity of immune microenvironment in hepatocellular carcinoma (HCC) remains elusive. Here, a single‐cell study involving 17 432 600 immune cells of 39 matched HCC (T), nontumor (N), and leading‐edge (L) specimens by mass cytometry is conducted. The tumor‐associated CD4/CD8 double‐positive T (DPT) cells are found enriched in L regions with synergetic expression of PD‐1/HLA‐DR/ICOS/CD45RO and exhibit a higher level of IFN‐ γ , TNF‐ α , and PD‐1 upon stimulation. The enrichment of DPT and PD‐1 + DPT in L regions indicates favorable prognosis. These tumor‐associated DPT cells with similar phenotype are also verified in other tumors and HCC animal models. Single‐cell RNA‐seq further characterizes the molecular features of DPT cells and uncovers 11 clusters with different cytotoxicity, exhaustion, and activation scores. TCR‐based trajectory analysis reveals that tumor‐associated DPT clusters share separated ancestries with local CD4 + or CD8 + SPT cells rather than CD3 + PBMC cells. TCR clones with frequency above 10 are mainly found coexisting in DPT and CD8 + SPT cells. Specifically, PD‐1 high DPT cluster (TDPT_10) shares the same ancestry with exhausted CD8 + SPT cluster (TCD8T_2) and shows higher expression similarity and closer pathological location to PD‐1 + CD8 + than PD‐1 + CD4 + T cells. Together, this study systematically characterizes the unique distribution of PD‐1 + DPTs in HCC and puts forward new insights for the function and origin of tumor‐associated DPT cells.
    Materialart: Online-Ressource
    ISSN: 2198-3844 , 2198-3844
    URL: Issue
    URL: Article
    DOI: 10.1002/advs.v7.13
    DOI: 10.1002/advs.202000224
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2020
    ZDB Id: 2808093-2
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    Online-Ressource
    Online-Ressource
    Comprehensive analysis of spatial architecture in primary liver cancer
    American Association for the Advancement of Science (AAAS) ; 2021
    In:  Science Advances Vol. 7, No. 51 ( 2021-12-17)
    Details
    In: Science Advances, American Association for the Advancement of Science (AAAS), Vol. 7, No. 51 ( 2021-12-17)
    Kurzfassung: Heterogeneity is the major challenge for cancer prevention and therapy. Here, we first constructed high-resolution spatial transcriptomes of primary liver cancers (PLCs) containing 84,823 spots within 21 tissues from seven patients. The progressive comparison of spatial tumor microenvironment (TME) characteristics from nontumor to leading-edge to tumor regions revealed that the tumor capsule potentially affects intratumor spatial cluster continuity, transcriptome diversity, and immune cell infiltration. Locally, we found that the bidirectional ligand-receptor interactions at the 100-μm-wide cluster-cluster boundary contribute to maintaining intratumor architecture and the PROM1 + and CD47 + cancer stem cell niches are related to TME remodeling and tumor metastasis. Last, we proposed a TLS-50 signature to accurately locate tertiary lymphoid structures (TLSs) spatially and unveiled that the distinct composition of TLSs is shaped by their distance to tumor cells. Our study provides previous unknown insights into the diverse tumor ecosystem of PLCs and has potential benefits for cancer intervention.
    Materialart: Online-Ressource
    ISSN: 2375-2548
    URL: Article
    DOI: 10.1126/sciadv.abg3750
    Sprache: Englisch
    Verlag: American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 2021
    ZDB Id: 2810933-8
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
    Online-Ressource
    Online-Ressource
    The identification and functional analysis of CD8+PD-1+CD161+ T cells in hepatocellular carcinoma
    Springer Science and Business Media LLC ; 2020
    In:  npj Precision Oncology Vol. 4, No. 1 ( 2020-10-30)
    Details
    In: npj Precision Oncology, Springer Science and Business Media LLC, Vol. 4, No. 1 ( 2020-10-30)
    Kurzfassung: 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.
    Materialart: Online-Ressource
    ISSN: 2397-768X
    URL: Article
    DOI: 10.1038/s41698-020-00133-4
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2020
    ZDB Id: 2891458-2
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 6
    Online-Ressource
    Online-Ressource
    Discovery of a Carbamoyl Phosphate Synthetase 1–Deficient HCC Subtype With Therapeutic Potential Through Integrative Genomic and Experimental Analysis
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Hepatology Vol. 74, No. 6 ( 2021-12), p. 3249-3268
    Details
    In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 74, No. 6 ( 2021-12), p. 3249-3268
    Kurzfassung: Metabolic reprogramming plays an important role in tumorigenesis. However, the metabolic types of different tumors are diverse and lack in‐depth study. Here, through analysis of big databases and clinical samples, we identified a carbamoyl phosphate synthetase 1 (CPS1)‐deficient hepatocellular carcinoma (HCC) subtype, explored tumorigenesis mechanism of this HCC subtype, and aimed to investigate metabolic reprogramming as a target for HCC prevention. Approach and Results A pan‐cancer study involving differentially expressed metabolic genes of 7,764 tumor samples in 16 cancer types provided by The Cancer Genome Atlas (TCGA) demonstrated that urea cycle (UC) was liver‐specific and was down‐regulated in HCC. A large‐scale gene expression data analysis including 2,596 HCC cases in 7 HCC cohorts from Database of HCC Expression Atlas and 17,444 HCC cases from in‐house hepatectomy cohort identified a specific CPS1‐deficent HCC subtype with poor clinical prognosis. In vitro and in vivo validation confirmed the crucial role of CPS1 in HCC. Liquid chromatography–mass spectrometry assay and Seahorse analysis revealed that UC disorder (UCD) led to the deceleration of the tricarboxylic acid cycle, whereas excess ammonia caused by CPS1 deficiency activated fatty acid oxidation (FAO) through phosphorylated adenosine monophosphate–activated protein kinase. Mechanistically, FAO provided sufficient ATP for cell proliferation and enhanced chemoresistance of HCC cells by activating forkhead box protein M1. Subcutaneous xenograft tumor models and patient‐derived organoids were employed to identify that blocking FAO by etomoxir may provide therapeutic benefit to HCC patients with CPS1 deficiency. Conclusions In conclusion, our results prove a direct link between UCD and cancer stemness in HCC, define a CPS1‐deficient HCC subtype through big‐data mining, and provide insights for therapeutics for this type of HCC through targeting FAO.
    Materialart: Online-Ressource
    ISSN: 0270-9139 , 1527-3350
    URL: Article
    DOI: 10.1002/hep.32088
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2021
    ZDB Id: 1472120-X
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
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