دورية أكاديمية
Using mouse liver cancer models based on somatic genome editing to predict immune checkpoint inhibitor responses.
| العنوان: | Using mouse liver cancer models based on somatic genome editing to predict immune checkpoint inhibitor responses. |
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| المؤلفون: | Yuen VW; Department of Pathology; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China., Chiu DK; Department of Pathology., Law CT; Department of Pathology., Cheu JW; Department of Pathology; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China., Chan CY; Department of Pathology; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China., Wong BP; Department of Pathology; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China., Goh CC; Department of Pathology., Zhang MS; Department of Pathology; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China., Xue HD; Department of Pathology; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China., Tse AP; Department of Pathology; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China., Zhang Y; Department of Pathology; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China., Lau HY; Department of Pathology., Lee D; Department of Pathology; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China., Au-Yeung RKH; Department of Pathology; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China., Wong CM; Department of Pathology; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong., Wong CC; Department of Pathology; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China. Electronic address: carmencl@pathology.hku.hk. |
| المصدر: | Journal of hepatology [J Hepatol] 2023 Feb; Vol. 78 (2), pp. 376-389. Date of Electronic Publication: 2022 Nov 29. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8503886 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1600-0641 (Electronic) Linking ISSN: 01688278 NLM ISO Abbreviation: J Hepatol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2001- : Amsterdam : Elsevier Original Publication: Copehnagen : Munksgaard International Publishers, [c1984- |
| مواضيع طبية MeSH: | Liver Neoplasms*/drug therapy , Liver Neoplasms*/genetics , Liver Neoplasms*/metabolism , Carcinoma, Hepatocellular*/drug therapy , Carcinoma, Hepatocellular*/genetics , Carcinoma, Hepatocellular*/metabolism, Humans ; Mice ; Animals ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Sorafenib/pharmacology ; Sorafenib/therapeutic use ; Kelch-Like ECH-Associated Protein 1/genetics ; Gene Editing ; CD8-Positive T-Lymphocytes ; NF-E2-Related Factor 2/genetics ; RNA/metabolism |
| مستخلص: | Background & Aims: Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) are the only two classes of FDA-approved drugs for individuals with advanced hepatocellular carcinoma (HCC). While TKIs confer only modest survival benefits, ICIs have been associated with remarkable outcomes but only in the minority of patients who respond. Understanding the mechanisms that determine the efficacy of ICIs in HCC will help to stratify patients likely to respond to ICIs. This study aims to elucidate how genetic composition and specific oncogenic pathways regulate the immune composition of HCC, which directly affects response to ICIs. Methods: A collection of mouse HCCs with genotypes that closely simulate the genetic composition found in human HCCs were established using genome-editing approaches involving the delivery of transposon and CRISPR-Cas9 systems by hydrodynamic tail vein injection. Mouse HCC tumors were analyzed by RNA-sequencing while tumor-infiltrating T cells were analyzed by flow cytometry and single-cell RNA-sequencing. Results: Based on the CD8 + T cell-infiltration level, we characterized tumors with different genotypes into cold and hot tumors. Anti-PD-1 treatment had no effect in cold tumors but was greatly effective in hot tumors. As proof-of-concept, a cold tumor (Trp53 KO /MYC OE ) and a hot tumor (Keap1 KO /MYC OE ) were further characterized. Tumor-infiltrating CD8 + T cells from Keap1 KO /MYC OE HCCs expressed higher levels of proinflammatory chemokines and exhibited enrichment of a progenitor exhausted CD8 + T-cell phenotype compared to those in Trp53 KO /MYC OE HCCs. The TKI sorafenib sensitized Trp53 KO /MYC OE HCCs to anti-PD-1 treatment. Conclusion: Single anti-PD-1 treatment appears to be effective in HCCs with genetic mutations driving hot tumors, while combined anti-PD-1 and sorafenib treatment may be more appropriate in HCCs with genetic mutations driving cold tumors. Impact and Implications: Genetic alterations of different driver genes in mouse liver cancers are associated with tumor-infiltrating CD8 + T cells and anti-PD-1 response. Mouse HCCs with different genetic compositions can be grouped into hot and cold tumors based on the level of tumor-infiltrating CD8 + T cells. This study provides proof-of-concept evidence to show that hot tumors are responsive to anti-PD-1 treatment while cold tumors are more suitable for combined treatment with anti-PD-1 and sorafenib. Our study might help to guide the design of patient stratification systems for single or combined treatments involving anti-PD-1. (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.) |
| فهرسة مساهمة: | Keywords: hepatocellular carcinoma; hydrodynamic tail vein injection; immunotherapy; preclinical models |
| المشرفين على المادة: | 0 (Immune Checkpoint Inhibitors) 9ZOQ3TZI87 (Sorafenib) 0 (Kelch-Like ECH-Associated Protein 1) 0 (NF-E2-Related Factor 2) 63231-63-0 (RNA) |
| تواريخ الأحداث: | Date Created: 20221201 Date Completed: 20230123 Latest Revision: 20230221 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1016/j.jhep.2022.10.037 |
| PMID: | 36455783 |
| قاعدة البيانات: | MEDLINE |
Full Text via ClinicalKey 
Full Text Finder | تدمد: | 1600-0641 |
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| DOI: | 10.1016/j.jhep.2022.10.037 |