Full metadata record
| DC Field | Value | Language |
|---|---|---|
| dc.contributor | Department of Applied Biology and Chemical Technology | en_US |
| dc.contributor.advisor | Lee, Kin Wah Terence (ABCT) | en_US |
| dc.creator | Chu, Chin Ngok | - |
| dc.identifier.uri | https://theses.lib.polyu.edu.hk/handle/200/14297 | - |
| dc.language | English | en_US |
| dc.publisher | Hong Kong Polytechnic University | en_US |
| dc.rights | All rights reserved | en_US |
| dc.title | Identification of MINK1 in modulating anti-tumor immunity in hepatocellular carcinoma using an in Vivo kinome CRISPR screen | en_US |
| dcterms.abstract | HCC is the third most lethal cancer and sixth most commonly diagnosed cancer worldwide. Emerging trends in immunotherapy, which have shown higher efficiency and better patient survival, have revolutionized the clinical management of HCC. Despite advances in therapeutic strategies, the low response rate to immune checkpoint inhibitors (ICI) remains a major hurdle in HCC treatment. Therefore, there is an urgent need to study the mechanisms of cancer–immune evasion. | en_US |
| dcterms.abstract | Kinase inhibitors are a popular treatment option for patients with cancer. The focus of kinase inhibitors has recently shifted from targeting pathways related to tumor proliferation to pathways related to immune regulation, as an increasing number of studies have reported the role of kinases in immune escape and ICI resistance. Therefore, we hypothesized that kinase inhibitors would enhance anti-tumor immune responses in HCC. Using an in vivo CRISPR knockout screening approach, we injected RIL-175 cells transduced with a kinome-pooled library into immunocompetent wildtype (WT) mice and immunodeficient Rag1-KO mice, and identified protein kinases crucial for immune modulation in HCC. Of all the protein kinases identified, MINK1 (Misshapen Like Kinase 1) showed the most significant result, with all RIL-175 cells with Mink1 knockout depleted in immunocompetent mice. The clinical relevance of MINK1 in HCC was confirmed by analysis of TCGA-LIHC and GEO cohorts, showing that overexpression of MINK1 promotes poor prognosis in HCC patients. Moreover, the TIDE web-based tool suggested that MINK1 overexpression was positively correlated with T cell dysfunction in patients with HCC. To functionally characterize the role of MINK1 in HCC, subcutaneous mouse models with Mink1 knockout have been developed. We observed tumor growth in immunocompetent mice, but not in immunodeficient mice, in Mink1 knockout mouse models. | en_US |
| dcterms.abstract | We further elucidated the mechanisms by which MINK1 affects the immune environment in HCC by a Mink1 overexpression mouse model. Using bulk RNA sequencing analysis, we observed enrichment in inflammation-related pathways and inflammatory factors Il-6 and Csf3, in addition to the downregulation of gene sets linked to T cells, suggesting that Mink1 overexpression may induce changes in gene networks associated with immune microenvironment remodeling and a robust inflammatory response. Mink1 contributes to the immunosuppressive TME, as evidenced by a reduction in CD8⁺ T cells and a substantial increase in neutrophil infiltration in our Mink1 overexpression model. We performed single-cell RNA sequencing (scRNA-seq) to gain comprehensive insight into the interactions between tumors and neutrophils. Neutrophil increases in tumors belong to the Mmp9-expressing and Pd-l1-expressing populations. Moreover, we observed increased Pd-1 and Pd-l1 expression in T cells and neutrophils. GSEA analysis showed the IL6/JAK/STAT3 pathway was upregulated in the neutrophil population in the Mink1 overexpression sample. | en_US |
| dcterms.abstract | In summary, this study identified Mink1 as a novel regulator of HCC immune evasion and revealed the mechanism by which Mink1 regulates HCC immune evasion is driven by IL-6- and CSF3-induced neutrophil recruitment and suppression of T cell function through PD-1 and PD-L1 interactions between neutrophils and T cells. Increased MMP9 expression may be regulated by the IL6/JAK/STAT3 pathway in neutrophils. | en_US |
| dcterms.extent | xvii, 151 pages : color illustrations | en_US |
| dcterms.isPartOf | PolyU Electronic Theses | en_US |
| dcterms.issued | 2023 | en_US |
| dcterms.educationalLevel | M.Phil. | en_US |
| dcterms.educationalLevel | All Master | en_US |
| dcterms.LCSH | Protein kinases | en_US |
| dcterms.LCSH | Cancer -- Immunological aspects | en_US |
| dcterms.LCSH | Liver -- Cancer -- Immunotherapy | en_US |
| dcterms.LCSH | Hong Kong Polytechnic University -- Dissertations | en_US |
| dcterms.accessRights | open access | en_US |
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