Journal Article

CCL5/CCR5/CYP1A1 pathway prompts liver cancer cells to survive in the combination of targeted and immunological therapies

Lu, Shichun, Wang, Yafei, Shi, Huizhong, Gao, Biao, Li, Xuerui, Jiang, Hao, Zhang, Wenwen, Pan, Ke, Jiao, Tianyu, Ge, Xinlan, Li, Junfeng, Mao, Guankun, Li, Chonghui

2024

Overview

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. Hepatocellular carcinoma (HCC) tissue possessed a stronger metabolic reprogramming capacity for lenvatinib compared with liver tissue during the combination theapy based on anti‐PD1 antibody plus lenvatinib, as reflected by the activation of the CCL5/CCR5/CYP1A1 pathway. CYP1A1 inhibitor could improve the efficacy of lenvatinib or combination therapy for HCC.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Animals / Antibodies / Apoptosis / bergamottin / Cancer therapies / Carcinoma, Hepatocellular - drug therapy / Carcinoma, Hepatocellular - immunology / Carcinoma, Hepatocellular - metabolism / Carcinoma, Hepatocellular - pathology / CC chemokine receptors / CCL5/CCR5/CYP1A1 / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell death / Cell Line, Tumor / Cell Survival - drug effects / Cells / Chemokine CCL5 - metabolism / Chemokines / Chemotherapy / Cloning / Combination therapy / Cytochrome P-450 CYP1A1 - genetics / Cytochrome P-450 CYP1A1 - metabolism / Cytochrome P450 / Cytokines / Cytotoxicity / Drug Resistance, Neoplasm / Growth factors / HCC / Hepatocellular carcinoma / Hepatocytes / Hepatoma / Humans / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / Immunohistochemistry / Immunotherapy / Immunotherapy - methods / Kinases / lenvatinib / Liver cancer / Liver Neoplasms - drug therapy / Liver Neoplasms - immunology / Liver Neoplasms - metabolism / Liver Neoplasms - pathology / Lymphocytes / Lymphocytes T / Male / Medical prognosis / Medical research / Mice / Original / ORIGINAL ARTICLE / Phenylurea Compounds - pharmacology / Proteins / Quinolines - pharmacology / Receptors, CCR5 - metabolism / Ribonucleic acid / RNA / Signal Transduction - drug effects / Software / Surgery / Tumor cells / Tumor necrosis factor-TNF / Tumors / Tyrosine kinase inhibitors / Xenograft Model Antitumor Assays