1. MAIT cells confer resistance to Lenvatinib plus anti-PD1 antibodies in hepatocellular carcinoma through TNF-TNFRSF1B pathway.
- Author
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Zhou, Cheng, Sun, Bao-Ye, Zhou, Pei-yun, Yang, Zhang-Fu, Wang, Zhu-Tao, Liu, Gao, Gan, Wei, Wang, Zheng, Zhou, Jian, Fan, Jia, Yi, Yong, Ren, Ning, and Qiu, Shuang-Jian
- Subjects
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HEPATOCELLULAR carcinoma , *REGULATORY T cells , *IMMUNE checkpoint inhibitors , *IMMUNOGLOBULINS , *NEOVASCULARIZATION inhibitors - Abstract
The combination of antiangiogenic agents and immune checkpoint inhibitors is more efficient than monotherapy in the management of hepatocellular carcinoma (HCC). Lenvatinib plus anti-PD1 antibodies have become the mainstay in HCC treatment. However, more than half the patients with HCC are non-responsive, and the mechanisms underlying drug resistance are unknown. To address this issue, we performed single-cell sequencing on samples from six HCC patients, aiming to explore cellular signals and molecular pathways related to the effect of lenvatinib plus anti-PD1 antibody treatment. GSVA analysis revealed that treatment with lenvatinib plus anti-PD1 antibody led to an increase in the TNF-NFKB pathway across all immune cell types, as compared to the non-treatment group. Mucosal-associated invariant T (MAIT) cells were found to secrete TNF, which activates TNFRSF1B on regulatory T cells, thereby promoting immunosuppression. Additionally, TNFSF9 was highly expressed in anticancer immune cells, including CD8+ effector T cells, MAIT, and γδ T cells in the treatment group. We also detected CD3+ macrophages in both HCC and pan-cancer tissues. Overall, our findings shed light on the potential mechanisms behind the effectiveness of lenvatinib plus anti-PD1 antibody treatment in HCC patients. By understanding these mechanisms better, we may be able to develop more effective treatment strategies for patients who do not respond to current therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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