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. 2023 Jul 17;7(8):e0209.
doi: 10.1097/HC9.0000000000000209. eCollection 2023 Aug 1.

Lenvatinib recruits cytotoxic GZMK+CD8 T cells in hepatocellular carcinoma

Tomoharu Yamada  1 , Naoto Fujiwara  2 , Naoto Kubota  3 , Yuki Matsushita  1 , Takuma Nakatsuka  1 , Shigeyuki Kurosaki  1 , Tatsuya Minami  1 , Ryosuke Tateishi  1 , Akihiko Ichida  4 , Junichi Arita  5 , Kiyoshi Hasegawa  4 , Kazuhiko Koike  1 , Mitsuhiro Fujishiro  1 , Hayato Nakagawa  1   2
Affiliations

Lenvatinib recruits cytotoxic GZMK+CD8 T cells in hepatocellular carcinoma

Tomoharu Yamada et al. Hepatol Commun. .

Abstract

Background: Lenvatinib was expected to enhance the effect of immune checkpoint inhibitors (ICIs) for unresectable HCC; however, their combination therapy failed to show the synergy in the phase III clinical trial.

Methods: To elucidate lenvatinib-induced molecular modulation, we performed bulk RNA-sequencing and digital spatial profiling of 5 surgically resected human HCC specimens after lenvatinib treatment and 10 matched controls without any preceding therapy.

Findings: Besides its direct antitumor effects, lenvatinib recruited cytotoxic GZMK+CD8 T cells in intratumor stroma by CXCL9 from tumor-associated macrophages, suggesting that lenvatinib-treated HCC is in the so-called excluded condition that can diminish ICI efficacy.

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Conflict of interest statement

Tomoharu Yamada received honoraria from Eisai and Chugai Pharmaceutical. Ryosuke Tateishi received honoraria from Eisai, Chugai Pharmaceutical, Bayer, and Takeda Pharmaceutical, and consultancies from Bayer. Kiyoshi Hasegawa received honoraria from Eisai, Chugai Pharmaceutical, Bayer, Eli Lilly, and Takeda Pharmaceutical, and grant support from Eisai, Chugai Pharmaceutical, Eli Lilly, and Takeda Pharmaceutical. Kazuhiko Koike received honoraria from Eisai, Chugai Pharmaceutical, Bayer, Eli Lilly, and Takeda Pharmaceutical, and grant support from Eisai, Chugai Pharmaceutical, and Takeda Pharmaceutical. Mitsuhiro Fujishiro received honoraria from Takeda Pharmaceutical. Hayato Nakagawa received honoraria from Eisai, Chugai Pharmaceutical, Eli Lilly, and Takeda Pharmaceutical. The remaining authors have no conflicts to report.

Figures

None
Graphical abstract
FIGURE 1
FIGURE 1
Lenvatinib recruits GZMK + CD8 cells into HCC. (A) Modulated pathways in lenvatinib-treated HCC compared with matched control HCCs by bulk transcriptome profiling. (B) Accumulated immune cells in lenvatinib-treated and control HCC. p-values were corrected by Bonferroni correction. (C) Gene signature–based immune cell characterization. (D) Accumulated GZMK+CD8 T cells in the intratumor stroma and HCC cell area. Arrowheads indicate GZMK+CD8 T cells. Scale bar, 250 μm. (E) Number of GZMK+CD8 T cells in the intratumor stroma and HCC cell area. (F) Representative image of region selection in the DSP. Scale bar, 3 mm. (G) Expression pattern of immune-related genes in GZMK+CD8+T-cell-rich, GZMK-CD8+T cell–rich, and GZMK-CD8- regions. Abbreviations: CXCL9, C-X-C motif chemokine ligand 9; DSP, digital spatial profiling; FDR, false discovery rate; GSEI, gene set enrichment index, GZMK, granzyme K; IQR, interquartile range; VEGFR, VEGRF receptor.
See this image and copyright information in PMC

References

    1. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16:589–604. - PMC - PubMed
    1. Kudo M, Finn RS, Qin S, Han K-H, Ikeda K, Piscaglia F, et al. . Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. The Lancet. 2018;391:1163–73. - PubMed
    1. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. . Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905. - PubMed
    1. Torrens L, Montironi C, Puigvehi M, Mesropian A, Leslie J, Haber PK, et al. . Immunomodulatory effects of lenvatinib plus anti-programmed cell death protein 1 in mice and rationale for patient enrichment in hepatocellular carcinoma. Hepatology. 2021;74:2652–69. - PubMed
    1. Lee WS, Yang H, Chon HJ, Kim C. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med. 2020;52:1475–85. - PMC - PubMed

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