PMID- 34458148
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210831
IS  - 2234-943X (Print)
IS  - 2234-943X (Electronic)
IS  - 2234-943X (Linking)
VI  - 11
DP  - 2021
TI  - Tyrosine Kinase Inhibitors Stimulate HLA Class I Expression by Augmenting the 
      IFNgamma/STAT1 Signaling in Hepatocellular Carcinoma Cells.
PG  - 707473
LID - 10.3389/fonc.2021.707473 [doi]
LID - 707473
AB  - Combination treatment with tyrosine kinase inhibitors (TKIs) and immunotherapies 
      has shown efficacy in the treatment of multiple cancers, but the immunomodulatory 
      effect of TKIs on the tumor cell phenotype remains unknown in hepatocellular 
      carcinoma (HCC). Given that human lymphocyte antigen class I (HLA-I) is essential 
      for tumor antigen presentation and subsequent antitumor immunity, we examined the 
      effects of regorafenib, as well as other TKIs (sorafenib, lenvatinib and 
      cabozantinib) on HLA-I expression in HCC cell lines. Regorafenib increased cell 
      surface HLA-I and beta2-microglobulin protein expression in the presence of 
      interferon gamma (IFNgamma). The expressions of various genes associated with the HLA-I 
      antigen processing pathway and its transcriptional regulators were also 
      upregulated by regorafenib. Furthermore, we found that regorafenib had an 
      activating effect on signal transducers and activators of transcription 1 
      (STAT1), and that regorafenib-induced HLA-I expression was dependent on the 
      augmented IFNgamma/STAT1 signaling pathway. Trametinib, an inhibitor of the 
      extracellular signal-regulated kinase (ERK) kinase MEK, also activated IFNgamma/STAT1 
      signaling and increased HLA-I expression, whereas the phosphatidylinositol 
      3-kinase (PI3K) inhibitor buparlisib did not. Given that regorafenib directly 
      inhibits Raf/MEK/ERK signaling, the downregulation of the MEK/ERK pathway appears 
      to be one of the mechanisms by which regorafenib promotes STAT1 activation. 
      Sorafenib, lenvatinib, and cabozantinib also showed the same effects as 
      regorafenib, while regorafenib had most potent effects on HLA-I expression, 
      possibly dependent on its stronger inhibitory activity against the MEK/ERK 
      pathway. These results support the clinical combination of TKIs with 
      immunotherapy for the treatment of HCC.
CI  - Copyright (c) 2021 Takahashi, Umemura, Yano, Okishio, Kataoka, Okuda, Seko, 
      Yamaguchi, Moriguchi, Okanoue and Itoh.
FAU - Takahashi, Aya
AU  - Takahashi A
AD  - Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, 
      Kyoto Prefectural University of Medicine, Kyoto, Japan.
FAU - Umemura, Atsushi
AU  - Umemura A
AD  - Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, 
      Kyoto Prefectural University of Medicine, Kyoto, Japan.
FAU - Yano, Kota
AU  - Yano K
AD  - Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, 
      Kyoto Prefectural University of Medicine, Kyoto, Japan.
FAU - Okishio, Shinya
AU  - Okishio S
AD  - Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, 
      Kyoto Prefectural University of Medicine, Kyoto, Japan.
FAU - Kataoka, Seita
AU  - Kataoka S
AD  - Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, 
      Kyoto Prefectural University of Medicine, Kyoto, Japan.
FAU - Okuda, Keiichiro
AU  - Okuda K
AD  - Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, 
      Kyoto Prefectural University of Medicine, Kyoto, Japan.
FAU - Seko, Yuya
AU  - Seko Y
AD  - Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, 
      Kyoto Prefectural University of Medicine, Kyoto, Japan.
FAU - Yamaguchi, Kanji
AU  - Yamaguchi K
AD  - Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, 
      Kyoto Prefectural University of Medicine, Kyoto, Japan.
FAU - Moriguchi, Michihisa
AU  - Moriguchi M
AD  - Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, 
      Kyoto Prefectural University of Medicine, Kyoto, Japan.
FAU - Okanoue, Takeshi
AU  - Okanoue T
AD  - Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka, 
      Japan.
FAU - Itoh, Yoshito
AU  - Itoh Y
AD  - Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, 
      Kyoto Prefectural University of Medicine, Kyoto, Japan.
LA  - eng
PT  - Journal Article
DEP - 20210811
PL  - Switzerland
TA  - Front Oncol
JT  - Frontiers in oncology
JID - 101568867
PMC - PMC8385668
OTO - NOTNLM
OT  - hepatocellular carcinoma
OT  - human lymphocyte antigen class I
OT  - mitogen-activated protein kinase
OT  - regorafenib
OT  - signal transducers and activators of transcription 1
OT  - tyrosine kinase inhibitor
COIS- YI received lecture fees from Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., 
      Takeda Pharmaceutical Company Limited, and Merck Sharp and Dohme, as well as 
      commercial research funding from Bayer AG, Eisai Co., Ltd., and Merck Sharp and 
      Dohme. MM received lecture fees from Bayer AG, Eisai Co., Ltd, Eli Lilly Japan 
      K.K., Chugai Pharmaceutical Co., Ltd. The remaining authors declare that the 
      research was conducted in the absence of any commercial or financial 
      relationships that could be construed as a potential conflict of interest.
EDAT- 2021/08/31 06:00
MHDA- 2021/08/31 06:01
PMCR- 2021/01/01
CRDT- 2021/08/30 06:00
PHST- 2021/05/10 00:00 [received]
PHST- 2021/07/27 00:00 [accepted]
PHST- 2021/08/30 06:00 [entrez]
PHST- 2021/08/31 06:00 [pubmed]
PHST- 2021/08/31 06:01 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fonc.2021.707473 [doi]
PST - epublish
SO  - Front Oncol. 2021 Aug 11;11:707473. doi: 10.3389/fonc.2021.707473. eCollection 
      2021.