한빛사논문
- 조회364
Sri Murugan Poongkavithai Vadevoo1,2,3,*, Yeoul Kang4,*, Gowri Rangaswamy Gunassekaran1,2,3, Seok-Min Lee1,2,3, Min-Sung Park1,2,3, Dong Gyun Jo1,2,3, Sang-Kyun Kim5, Ho Lee6, Won Jong Kim4, Byungheon Lee1,2,3
1Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea.
2Department of Biomedical Science, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea.
3CMRI, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea.
4Department of Chemistry, POSTECH-CATHOLIC Biomedical Engineering Institute, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk 37673, Republic of Korea.
5Laboratory Animal Center, K-Medi Hub, 88 Dongnae-ro, Dong-gu, Daegu 41061, Republic of Korea.
6Laboratory Animal Research Facility, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Koyang, Kyunggi 10408, Republic of Korea.
* These authors equally contributed.
Corresponding authors: Byungheon Lee, Won Jong Kim
Abstract
Rationale: Nab-paclitaxel (Abx) is widely employed in malignant tumor therapy. In tumor cells and pro-tumoral M2-type macrophages, the IL4 receptor (IL4R) is upregulated. This study aimed to elucidate the selective delivery of Abx to M2-type macrophages by targeting IL4R and reprogramming them into an anti-tumoral M1-type.
Methods: Abx was conjugated with the IL4R-binding IL4RPep-1 peptide using click chemistry (IL4R-Abx). Cellular internalization, macrophage reprogramming and signal pathways, and tumor growth and metastasis by IL4R-Abx were examined.
Results: IL4R-Abx was internalized into M2 macrophages more efficiently compared to the unmodified Abx and control peptide-conjugated Abx (Ctrl-Abx), which was primarily inhibited using an anti-IL4R antibody and a receptor-mediated endocytosis inhibitor compared with a macropinocytosis inhibitor. IL4R-Abx reprogrammed the M2-type macrophages into M1-like phenotype and increased reactive oxygen species (ROS) levels and extracellular release of high mobility group box 1 (HMGB1) in M2 macrophages at higher levels than Abx and Ctrl-Abx. The conditioned medium of IL4R-Abx-treated M2 macrophages skewed M2 macrophages into the M1-like phenotype, in which an anti-HMGB1 antibody and a toll-like receptor 4 (TLR4) inhibitor induced a blockade. IL4R-Abx accumulated at tumors, heightened immune-stimulatory cells while reducing immune-suppressing cells, and hampered tumor growth and metastasis in mice more efficiently than Abx and Ctrl-Abx.
Conclusions: These results indicate that IL4R-targeting allows enhancement of M2-macrophage shaping into M1-like phenotype by Abx through the ROS-HMGB1-TLR4 axis, improvement of antitumor immunity, and thereby inhibition of tumor growth and metastasis, presenting a new approach to cancer immunotherapy.
논문정보
- Research article
- 2024년 04월 (BRIC 등록일 2024-04-14)
- 국내 연구진
- 의약학 > 종양의학
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