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ID 119228
Title Alternative
抗ポドプラニン抗体はナチュラルキラー細胞による悪性中皮腫に対する抗CTLA-4抗体の抗腫瘍効果を増強する
Author
Yoneda, Hiroto Tokushima University
Yoshida, Aito Tokushima University
Ogino, Hirokazu Tokushima University
Itakura, Satoshi Tokushima University
Nguyen, Na Thi Tokushima University
Nokihara, Hiroshi Tokushima University
Kaneko, Mika K. Tohoku University
Kato, Yukinari Tohoku University
Keywords
CTLA-14
NK cell
Immune checkpoint inhibitor
Malignant pleural mesothelioma
Podoplanin
Content Type
Thesis or Dissertation
Description
Combination immunotherapy with multiple immune checkpoint inhibitors (ICIs) has been approved for various types of malignancies, including malignant pleural mesothelioma (MPM). Podoplanin (PDPN), a transmembrane sialomucin-like glycoprotein, has been investigated as a diagnostic marker and therapeutic target for MPM. We previously generated and developed a PDPN-targeting Ab reagent with high Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, the effects of anti-PDPN Abs on various tumor-infiltrating immune cells and their synergistic effects with ICIs have remained unclear. In the present study, we established a novel rat–mouse chimeric anti- mouse PDPN IgG2a mAb (PMab-1-mG2a) and its core-fucose-deficient Ab (PMab-1-mG2a-f) to address these limitations. We identified the ADCC and CDC activity of PMab-1-mG2a-f against the PDPN-expressing mesothelioma cell line AB1-HA. The antitumor effect of monotherapy with PMab-1-mG2a-f was not sufficient to overcome tumor progression in AB1-HA-bearing immunocompetent mice. However, PMab-1-mG2a-f enhanced the antitumor effects of CTLA-4 blockade. Combination therapy with anti-PDPN Ab and anti-CTLA-4 Ab increased tumor-infiltrating natural killer (NK) cells. The depletion of NK cells inhibited the synergistic effects of PMab-1-mG2a-f and CTLA-4 blockade in vivo. These findings indicated the essential role of NK cells in novel combination immunotherapy targeting PDPN and shed light on the therapeutic strategy in advanced MPM.
Journal Title
Cancer Science
ISSN
13479032
13497006
Publisher
Japanese Cancer Association|John Wiley & Sons
Volume
115
Issue
2
Start Page
357
End Page
368
Published Date
2023-12-26
Remark
内容要旨・審査要旨・論文本文の公開
本論文は, 著者Hiroto Yoneda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。
Rights
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
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3835号
Diploma Number
甲医第1612号
Granted Date
2024-06-27
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
University Hospital
Medical Sciences
Pharmaceutical Sciences