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CCL5/CCR5/CYP1A1 pathway prompts liver cancer cells to survive in the combination of targeted and immunological therapies.
- Source :
-
Cancer science [Cancer Sci] 2024 Nov; Vol. 115 (11), pp. 3552-3569. Date of Electronic Publication: 2024 Aug 25. - Publication Year :
- 2024
-
Abstract
- Combination therapy of anti-programmed cell death protein-1 (PD-1) antibodies and tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis for hepatocellular carcinoma (HCC), but many patients still have unsatisfactory outcomes. CD8 T cells are known to exert a pivotal function in the immune response against tumors. Nevertheless, most CD8 T cells in HCC tissues are in a state of exhaustion, losing the cytotoxic activity against malignant cells. Cytokines, mainly secreted by immune cells, play an important role in the occurrence and development of tumors. Here, we demonstrated the changes in exhausted CD8T cells during combination therapy by single-cell RNA sequencing (scRNA-seq) analysis on tumor samples before and after treatment. Combination therapy exerted a substantial impact on the exhausted CD8T cells, particularly in terms of cytokine expression. CCL5 was the most abundantly expressed cytokine in CD8T cells and exhausted CD8T cells, and its expression increased further after treatment. Subsequently, we discovered the CCL5/CCR5/CYP1A1 pathway through RNA sequencing (RNA-seq) on CCL5-stimulated Huh7 cells and verified through a series of experiments that this pathway can mediate the resistance of liver cancer cells to lenvatinib. Tissue experiments showed that after combination therapy, the CCL5/CCR5/CYP1A1 pathway was activated, which can benefit the residual tumor cells to survive treatment. Tumor-bearing mouse experiments demonstrated that bergamottin (BGM), a competitive inhibitor of CYP1A1, can enhance the efficacy of both lenvatinib and combination therapy. Our research revealed one mechanism by which hepatoma cells can survive the combination therapy, providing a theoretical basis for the refined treatment of HCC.<br /> (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Subjects :
- Humans
Animals
Mice
Cell Line, Tumor
Signal Transduction drug effects
Xenograft Model Antitumor Assays
Immune Checkpoint Inhibitors pharmacology
Immune Checkpoint Inhibitors therapeutic use
Cell Survival drug effects
Immunotherapy methods
Drug Resistance, Neoplasm
Male
Liver Neoplasms drug therapy
Liver Neoplasms metabolism
Liver Neoplasms pathology
Liver Neoplasms immunology
Carcinoma, Hepatocellular drug therapy
Carcinoma, Hepatocellular metabolism
Carcinoma, Hepatocellular pathology
Carcinoma, Hepatocellular immunology
CD8-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes metabolism
Chemokine CCL5 metabolism
Phenylurea Compounds pharmacology
Quinolines pharmacology
Receptors, CCR5 metabolism
Cytochrome P-450 CYP1A1 metabolism
Cytochrome P-450 CYP1A1 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1349-7006
- Volume :
- 115
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cancer science
- Publication Type :
- Academic Journal
- Accession number :
- 39183447
- Full Text :
- https://doi.org/10.1111/cas.16320