Comprehensive Management of Hepatocellular Carcinoma Targeting Innate Immunological Escape of the Cancer
| Project/Area Number |
19H03633
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | Chiba University |
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Principal Investigator |
Kato Naoya 千葉大学, 大学院医学研究院, 教授 (90313220)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
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| Keywords | 肝癌 / 自然免疫 / 発癌抑止 / MICA / NK細胞 / PD-L1 / ADAM / 細胞傷害性T細胞 / 肝細胞癌 |
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| Outline of Research at the Start |
肝癌は多中心性発癌を特徴とする。ウイルス性慢性肝炎の治療が確立し、肝発癌抑止は最重要アンメット・ニーズである。われわれはゲノムワイド関連解析により肝癌感受性遺伝子MICAを同定した。Kill meシグナルであるMICA発現肝細胞をNK細胞が排除することが肝発癌抑止に重要である。しかし、肝癌細胞はMICA切断酵素を発現し自然免疫機構から逃避しており、その機構を標的とした発癌抑止法の開発を目指す。
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| Outline of Final Research Achievements |
MICA is expressed on the surface of hepatocellulara carcinoma (HCC) cells and is a target of NK cells, but HCC cells cleave MICA to evade NK cell attack. 1) We identified ADAM9/10/17 as MICA cleaving enzymes. 2) MICA expression was upregulated in HCC tissues, but MICA cleavage resulted in low NK cell invasion into the tissues. 3) Screening of ADAM9 inhibitors identified two leukotriene antagonists and an acyclic retinoid. 4) ADAM9 also cleaved membrane PD-L1 and evaded the acquired immunity mechanism. These findings suggest that ADAM9 inhibition may be useful for the treatment of HCC and prevention of hepatocarcinogenesis by stimulating innate and acquired immunity against HCC.
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| Academic Significance and Societal Importance of the Research Achievements |
ほとんどのC型肝炎症例でウイルス排除が可能となったが発癌は十分に抑止できていない。C型肝癌に対する薬物療法は複合免疫療法が第一選択となったがその効果はいまだ満足するレベルに達していない。したがって、新たな発癌抑止法、肝癌治療法の開発が急務である。肝癌細胞に表出している自然および獲得免疫の標的となる分子であるMICA、PD-L1のADAM9/10/17による切断が肝癌細胞の免疫逃避機構の一翼を担っており、それらの切断阻害は自然免疫賦活による新たな発癌抑止法となる可能性、また、肝癌細胞に対する自然免疫賦活+獲得免疫賦活による新たな肝癌治療法となる可能性があると期待される。
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Report
(4 results)
Research Products
(24 results)
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[Journal Article] Baseline soluble MICA levels act as a predictive biomarker for the efficacy of regorafenib treatment in colorectal cancer2021
Author(s)
Arai J, Otoyama Y, Fujita KI, Goto K, Tojo M, Katagiri A, Nozawa H, Kubota Y, Takahashi T, Ishida H, Tsunoda T, Matsumoto N, Ogawa K, Nakagawa R, Muroyama R, Kato N, Yoshida H.
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Journal Title
BMC Cancer
Volume: 22
Pages: 428-428
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Retinoids decrease soluble MICA concentration by inhibiting the enzymatic activity of ADAM9 and ADAM102021
Author(s)
Otoyama Y, Arai J, Goto K, Nozawa H, Nakagawa R, Muroyama R, Sugiura I, Nakajima Y, Kajiwara A, Tojo M, Ichikawa Y, Uozumi S, Shimozuma Y, Uchikoshi M, Sakaki M, Kato N, Yoshida H.
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Journal Title
Anticancer Res
Volume: 41
Pages: 2307-2320
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Leukotriene receptor antagonists enhance HCC treatment efficacy by inhibiting ADAMs and suppressing MICA shedding2021
Author(s)
Arai J, Goto K, Otoyama Y, Nakajima Y, Sugiura I, Kajiwara A, Tojo M, Ichikawa Y, Uozumi S, Shimozuma Y, Uchikoshi M, Sakaki M, Nozawa H, Nakagawa R, Muroyama R, Kato N, Yoshida H.
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Journal Title
Cancer Immunology, Immunotherapy
Volume: 70
Pages: 203-213
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Regorafenib and its metabolotes could Induce NK cell-mediated cytotoxixity in HCC by targeting ADAM92021
Author(s)
Arai J, Otoyama Y, Goto K, Nakagawa R, Muroyama R, Ogawa K, Sugiura I, Nakajima Y, Kajiwara A, Ichikawa Y, Uozumi S, Shimozuma Y, Uchikoshi M, Sakaki M, Kato N, Yohida H
Organizer
APASL oncology 2021
Related Report
Int'l Joint Research
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[Presentation] Novel immuno-oncotherapy against HCC by targeting MICA2021
Author(s)
Otoyama Y, Arai J, Goto K, Nakagawa R, Muroyama R, Sugiura I, Nakajima Y, Kajiwara A, Ichikawa Y, Uozumi S, Shimozuma Y, Uchikoshi M, Sakaki M, Kato N, Yoshida H
Organizer
APASL oncology 2021
Related Report
Int'l Joint Research
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[Presentation] Development of novel therapeutic agents for HCC by suppressing soluble MICA through ADAM9 inhibition2021
Author(s)
Ogawa K, Nakagawa R, Ao J, Qiamg N, Ma Y, Zhang J, Iwanaga T, Sakuma T, Kanzaki H, Kobayashi K, Nakamura M, Kanogawa N, Kondo T, Ogasawara S, Muroyama R, Nakamoto S, Chiba T, Kanda T, Maruyama H, Kato N
Organizer
APASL oncology 2021
Related Report
Int'l Joint Research
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[Presentation] Screening of ADAM9 inhibitors for suppression of soluble MICA in hepatocellular carcinoma2021
Author(s)
Ogawa K, Nakagawa R, Ishino T, Iwanaga T, Unozawa H, Fujiwara K, Nakagawa M, Sakuma T, Fujita N, Kanzaki H, Koroki K, Kobayashi K, Kiyono S, Nakamura M, Kanogawa N, Saito T, Kondo T, Ogasawara S, Muroyama R, Nakamoto S, Chiba T, Kato N
Organizer
AASLD 2021
Related Report
Int'l Joint Research
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[Presentation] 大腸癌に対するレゴラフェニブ治療においてMICAは加療効果予測のバイオマーカーになり得る2021
Author(s)
荒井潤, 後藤覚, 音山裕美, 杉浦育也, 中島陽子, 梶原敦, 市川雪, 魚住祥二郎, 下間祐, 打越学, 坂木理, 中川良, 室山良介, 加藤直也, 吉田仁
Organizer
JDDW 2021
Related Report
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[Presentation] レチノイドによるがん微小環境を標的とした肝がん治療戦略2021
Author(s)
音山裕美, 荒井潤, 後藤覚, 中島陽子, 杉浦育也, 梶原敦, 市川雪, 魚住祥二郎, 下間祐, 打越学, 坂木理, 中川良, 室山良介, 加藤直也, 吉田仁
Organizer
JDDW 2021
Related Report
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