한빛사논문
- 조회150
Eun Hye Kim1,2, Jiwoong Choi1, Hochung Jang1,3, Yelee Kim1,2, Jong Won Lee1,4, Youngri Ryu1,2, Jiwon Choi1,5, Yeonho Choi5, Sung-Gil Chi2, Ick Chan Kwon1,4, Yoosoo Yang1,3, Sun Hwa Kim1,4
1Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
2Department of Life Sciences, Korea University, Seoul 02841, Republic of Korea.
3Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea.
4KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea.
5Department of Bioengineering, Korea University, Seoul 02841, Republic of Korea.
Corresponding authors: Yoosoo Yang, Ph.D. (Y. Yang), Sun Hwa Kim, Ph.D. (S.H. Kim)
Abstract
Rationale: Growing evidence has demonstrated that miRNA-21 (miR-21) upregulation is closely associated with tumor pathogenesis. However, the mechanisms by which miR-21 inhibition modulates the immunosuppressive tumor microenvironment (TME) and improves tumor sensitivity to immune checkpoint blockade therapies remain largely unexplored. In this study, we demonstrate the precise delivery of anti-miR-21 using a PD-L1-targeting peptide conjugate (P21) to the PD-L1high TME.
Methods: Investigating miR-21 inhibition mechanisms involved conducting quantitative real-time PCR, western blot, flow cytometry, and confocal microscopy analyses. The antitumor efficacy and immune profile of P21 monotherapy, or combined with anti-PD-L1 immune checkpoint inhibitors, were assessed in mouse models bearing CT26.CL25 tumors and 4T1 breast cancer.
Results Inhibition of oncogenic miR-21 in cancer cells by P21 efficiently activates tumor suppressor genes, inducing autophagy and endoplasmic reticulum stress. Subsequent cell-death-associated immune activation (immunogenic cell death) is initiated via the release of damage-associated molecular patterns. The in vivo results also illustrated that the immunogenic cell death triggered by P21 could effectively sensitize the immunosuppressive TME. That is, P21 enhances CD8+ T cell infiltration in tumor tissues by conferring immunogenicity to dying cancer cells and promoting dendritic cell maturation. Meanwhile, combining P21 with an anti-PD-L1 immune checkpoint inhibitor elicits a highly potent antitumor effect in a CT26.CL25 tumor-bearing mouse model and 4T1 metastatic tumor model.
Conclusions: Collectively, we have clarified a miR-21-related immunogenic cell death mechanism through the precise delivery of anti-miR-21 to the PD-L1high TME. These findings highlight the potential of miR-21 as a target for immunotherapeutic interventions.
논문정보
- Research article
- 2024년 06월 (BRIC 등록일 2024-07-16)
- 국내 연구진
- 바이오·의료융합 > 바이오센싱 및 나노바이오물질
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