Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2025-01-30 DOI:10.1016/j.ccell.2025.01.001

Xinyi Guo, Hu Nie, Wenwen Zhang, Jiesheng Li, Jing Ge, Bowen Xie, Wenbo Hu, Yicheng Zhu, Na Zhong, Xinmei Zhang, Xiaohong Zhao, Xiaoshuang Wang, Qinli Sun, Kun Wei, Xiaoyuan Chen, Ling Ni, Ting Zhang, Shichun Lu, Lei Zhang, Chen Dong

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引用次数: 0

Abstract

Combination of anti-PD-1 with lenvatinib showed clinical efficacy in multiple cancers, yet the underlying immunological mechanisms are unclear. Here, we compared T cells in hepatocellular carcinoma (HCC) patients before and after combination treatment using single-cell transcriptomics and T cell receptor (scTCR) clonotype analyses. We found that tumor-infiltrating GZMK⁺ CD8⁺ effector/effector memory T (Teff/Tem) cells, showing a favorable response to combination therapy, comprise progenitor exhausted T (Tpex) cells and also unappreciated circulating Tem (cTem) cells enriched with hepatitis B virus (HBV) specificity. Further integrated analyses revealed that cTem cells are specifically associated with responsiveness to the combination therapy, whereas Tpex cells contribute to responses in both combination therapy and anti-PD-1 monotherapy. Notably, an underexplored KIR⁺ CD8⁺ T cell subset in the tumor and FOXP3⁺ CD4⁺ regulatory T cells are specifically enriched in non-responders after the combination therapy. Our study thus elucidated T cell subsets associated with clinical benefits and resistance in cancer immunotherapy.

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.