한빛사논문
- 조회149
Yoonjeong Choi1,2, Seong A Kim2,3, Hanul Jung1,4, Eunhae Kim1,2,3, Yoon Kyoung Kim1, Seohyun Kim1, Jaehyun Kim1, Yeji Lee2,3, Min Kyoung Jo5, Jiwan Woo6, Yakdol Cho6, Dongjoo Lee7, Hongyoon Choi7,8,9, Cherlhyun Jeong3,10, Gi-Hoon Nam1,5, Minsu Kwon4 and In-San Kim2,3
1SHIFTBIO INC, Seoul, Republic of Korea
2KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea
3Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea
4Department of Otolaryngology, University of Ulsan College of Medicine, Seoul, Republic of Korea
5Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea
6Research Animal Resource Center, Korea Institute of Science and Technology, Seoul, Republic of Korea
7Portrai Inc, Seoul, Republic of Korea
8Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea
9Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
10Division of Biomedical Science and Technology, KIST School, University of Science and Technology, Seoul, Republic of Korea
Correspondence to Dr In-San Kim; Dr Minsu Kwon; Dr Gi-Hoon Nam
YC and SAK are joint first authors.
Abstract
Background: Triple-negative breast cancer (TNBC) poses unique challenges due to its complex nature and the need for more effective treatments. Recent studies showed encouraging outcomes from combining paclitaxel (PTX) with programmed cell death protein-1 (PD-1) blockade in treating TNBC, although the exact mechanisms behind the improved results are unclear.
Methods: We employed an integrated approach, analyzing spatial transcriptomics and single-cell RNA sequencing data from TNBC patients to understand why the combination of PTX and PD-1 blockade showed better response in TNBC patients. We focused on toll-like receptor 4 (TLR4), a receptor of PTX, and its role in modulating the cross-presentation signaling pathways in tumor-associated macrophages (TAMs) within the tumor microenvironment. Leveraging insights obtained from patient-derived data, we conducted in vitro experiments using immunosuppressive bone marrow-derived macrophages (iBMDMs) to validate if PTX could augment the cross-presentation and phagocytosis activities. Subsequently, we extended our study to an in vivo murine model of TNBC to ascertain the effects of PTX on the cross-presentation capabilities of TAMs and its downstream impact on CD8+ T cell-mediated immune responses.
Results: Data analysis from TNBC patients revealed that the activation of TLR4 and cross-presentation signaling pathways are crucial for the antitumor efficacy of PTX. In vitro studies showed that PTX treatment enhances the cross-presentation ability of iBMDMs. In vivo experiments demonstrated that PTX activates TLR4-dependent cross-presentation in TAMs, improving CD8+ T cell-mediated antitumor responses. The efficacy of PTX in promoting antitumor immunity was elicited when combined with PD-1 blockade, suggesting a complementary interaction.
Conclusions: This study reveals how PTX boosts the effectiveness of PD-1 inhibitors in treating TNBC. We found that PTX activates TLR4 signaling in TAMs. This activation enhances their ability to present antigens, thereby boosting CD8+ T cell antitumor responses. These findings not only shed light on PTX's immunomodulatory role in TNBC but also underscore the potential of targeting TAMs' antigen presentation capabilities in immunotherapy approaches.
논문정보
- Research article
- 2024년 07월 (BRIC 등록일 2024-07-16)
- 국내 연구진
- 의약학 > 종양의학
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