Lenvatinib activates anti-tumor immunity by suppressing immunoinhibitory infiltrates in the tumor microenvironment of advanced hepatocellular carcinoma.

Autor:	Yamauchi M; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. myamauchi@hiroshima-u.ac.jp., Ono A; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., Amioka K; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., Fujii Y; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., Nakahara H; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.; Department of Clinical and Molecular Genetics, Hiroshima University, Hiroshima, Japan., Teraoka Y; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., Uchikawa S; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., Fujino H; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., Nakahara T; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., Murakami E; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., Okamoto W; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., Miki D; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., Kawaoka T; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., Tsuge M; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., Imamura M; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., Hayes CN; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., Ohishi W; Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima, Japan., Kishi T; Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima, Japan., Kimura M; Oncology Department, HQs, Eisai Co., Ltd, Tokyo, Japan., Suzuki N; Oncology Department, HQs, Eisai Co., Ltd, Tokyo, Japan., Arihiro K; Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan., Aikata H; Department of Gastroenterology, Hiroshima Prefectural Hospital, Hiroshima, Japan., Chayama K; Collaborative Research Laboratory of Medical Innovation, Hiroshima University, Hiroshima, Japan. chayama@mba.ocn.ne.jp.; Hiroshima Institute of Life Sciences, Hiroshima, Japan. chayama@mba.ocn.ne.jp.; RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. chayama@mba.ocn.ne.jp., Oka S; Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. oka4683@hiroshima-u.ac.jp.
Jazyk:	angličtina
Zdroj:	Communications medicine [Commun Med (Lond)] 2023 Oct 25; Vol. 3 (1), pp. 152. Date of Electronic Publication: 2023 Oct 25.
DOI:	10.1038/s43856-023-00390-x
Abstrakt:	Background: Lenvatinib, a multiple receptor tyrosine kinase inhibitor, might exert antitumor effects via tumor immune modulation. However, changes in the tumor immune microenvironment induced by lenvatinib are poorly understood. We investigated the effect of lenvatinib on immune features in clinical samples from patients with hepatocellular carcinoma. Methods: Fifty-one patients with advanced hepatocellular carcinoma who received lenvatinib monotherapy as first-line treatment were enrolled. We collected blood sample (n = 51) and tumor tissue (n, baseline/four weeks after treatment initiation/post-progression = 50/8/12). DNA, RNA, and proteins extracted from the tissues were subjected to multi-omics analysis, and patients were classified into two groups according to baseline immune status. Each group was investigated in terms of the dynamics of tumor signaling. We also longitudinally analyzed circulating immune proteins and chemokines in peripheral blood. Results: Here we show that lenvatinib has similar anti-tumor efficacy with objective response rate and progression-free survival in both Immune-Hot and Immune-Cold subtypes. Immune signatures associated with T-cell functions and interferon responses are enriched in the early phase of treatment, while signatures associated with immunoinhibitory cells are downregulated along with efficient vascular endothelial growth factor receptor and fibroblast growth factor receptor blockades. These findings are supported by imaging mass cytometry, T-cell receptor repertoire analysis and kinetics of circulating proteins. We also identify interleukin-8 and angiopoietin-2 as possible targets of intervention to overcome resistance to existing immunotherapies. Conclusions: Our findings show the ability of lenvatinib to modulate tumor immunity in clinical samples of hepatocellular carcinoma. (© 2023. Springer Nature Limited.)
Databáze:	MEDLINE
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