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조회318

University of Texas MD Anderson Cancer Center

Nat. Biomed. Eng., Apr 19 2024, | https://doi.org/10.1038/s41551-024-01194-7 Synthetic cationic helical polypeptides for the stimulation of antitumour innate immune pathways in antigen-presenting cells

DaeYong Lee ^1,2,6, Kristin Huntoon ^1,2,6, Yifan Wang^3,6, Minjeong Kang ³, Yifei Lu^1,2, Seong Dong Jeong ^1,2, Todd M. Link ⁴, Thomas D. Gallup ^1,2, Yaqing Qie ^1,2, Xuefeng Li ³, Shiyan Dong ³, Benjamin R. Schrank ³, Adam J. Grippin ³, Abin Antony³, JongHoon Ha³, Mengyu Chang³, Yi An ⁵, Liang Wang ³, Dadi Jiang ³, Jing Li ³, Albert C. Koong ³, John A. Tainer ⁴, Wen Jiang ^3,*& Betty Y. S. Kim ^1,2,*

¹Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²Brain Tumour Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA.
⁶These authors contributed equally: DaeYong Lee, Kristin Huntoon, Yifan Wang.

^*Corresponding authors: correspondence to Wen Jiang or Betty Y. S. Kim

Abstract

Intracellular DNA sensors regulate innate immunity and can provide a bridge to adaptive immunogenicity. However, the activation of the sensors in antigen-presenting cells (APCs) by natural agonists such as double-stranded DNAs or cyclic nucleotides is impeded by poor intracellular delivery, serum stability, enzymatic degradation and rapid systemic clearance. Here we show that the hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate innate immune pathways via endoplasmic reticulum stress in APCs. One of the three polypeptides that we engineered activated two major intracellular DNA-sensing pathways (cGAS-STING (for cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes) and Toll-like receptor 9) preferentially in APCs by promoting the release of mitochondrial DNA, which led to the efficient priming of effector T cells. In syngeneic mouse models of locally advanced and metastatic breast cancers, the polypeptides led to potent DNA-sensor-mediated antitumour responses when intravenously given as monotherapy or with immune checkpoint inhibitors. The activation of multiple innate immune pathways via engineered cationic polypeptides may offer therapeutic advantages in the generation of antitumour immune responses.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-04-22)
연구진국외 연구진
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