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胸部腫瘍において、S-1は腫瘍由来Bv8およびS100A8の制御を介してMDSCを除去しPD-1阻害薬の効果を増強する
著者
グエン, ナ チ 徳島大学大学院医学研究科(医学専攻)
香西, 博之 Tokushima University
米田, 浩人 Tokushima University
Afroj, Tania Tokushima University
軒原, 浩 Tokushima University
キーワード
oncology
immune checkpoint inhibitor
myeloid-derived suppressor cells
S-1
Bv8
S100A8
資料タイプ
学位論文
抄録
Myeloid-derived suppressor cells (MDSCs) have been known to play a pivotal role in the induction of immune tolerance, which limits the benefits of immune checkpoint inhibitors (ICIs). Recent studies revealed that several chemotherapeutic agents decreased tumor-infiltrating MDSCs. Therefore, combination therapy with cytotoxic chemotherapeutic agents and ICIs was approved for first-line treatment for lung cancer. However, the impact of chemotherapeutic agents on MDSCs and an optimal partner of ICIs has not been fully investigated in thoracic tumors, including lung cancer and malignant pleural mesothelioma. In the present study, we found that treatment with 5-FU and its oral formulation, S-1, suppressed tumor progression and inhibited the accumulation of MDSCs in thoracic tumor-bearing mice. Tumor-infiltrating T cells and dendritic cells were significantly expanded in S-1-treated mice. 5-FU suppressed the ability of tumor cells to recruit MDSCs, while it did not suppress the survival and differentiation of mouse MDSCs in vitro. We also revealed that 5-FU or S-1 significantly downregulated the expression of tumor-derived Bv8 and S100A8. The knockdown of Bv8 or S100A8 in tumor cells suppressed tumor growth and MDSC recruitment in vivo. Furthermore, in comparison with pemetrexed, administration of S-1 improved the synergistic therapeutic efficacy of anti-PD-1 antibodies with or without carboplatin. Our findings revealed a novel mechanism wherein S-1 primed a favorable tumor microenvironment to provide the rationale for combination therapy with S-1 and ICIs as the optimal therapy for thoracic cancer.
掲載誌名
Cancer Science
ISSN
13497006
出版者
Japanese Cancer Association|John Wiley & Sons
114
2
開始ページ
384
終了ページ
398
発行日
2022-10-26
備考
内容要旨・審査要旨・論文本文の公開
本論文は,著者Na T. Nguyenの学位論文として提出され,学位審査・授与の対象となっている。
権利情報
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
博士論文全文を含む
文科省報告番号
甲第3703号
学位記番号
甲医第1573号
学位授与年月日
2023-03-23
学位名
博士(医学)
学位授与機関
徳島大学
部局
医学系
病院