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

作者：Yafei Wang, Biao Gao, Tianyu Jiao, Wenwen Zhang, Huizhong Shi, Hao Jiang, Xuerui Li, Junfeng Li, Xinlan Ge, Ke Pan, Chonghui Li, Guankun Mao, Shichun Lu · 发表于：Cancer Science · 年份：2024 · DOI：10.1111/cas.16320 · 被引用次数：7 · 研究领域：Cancer Immunotherapy and Biomarkers、Immune cells in cancer、Chemokine receptors and signaling

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 bergamotti...