Ultrasound Control of Genomic Regulatory Toolboxes for Cancer Immunotherapy

Yiqian Wu; Ziliang Huang; Yahan Liu; Peixiang He; Yuxuan Wang; Liyanran Yan; Xinhui Wang; Shanzi Gao; Xintao Zhou; Chi Woo Yoon; Kun Sun; Yinglin Situ; Phuong Ho; Yushun Zeng; Zhou Yuan; Linshan Zhu; Qifa Zhou; Yunde Zhao; Thomas Liu; Gabriel A Kwong; Shu Chien; Longwei Liu; Yingxiao Wang

doi:10.1038/s41467-024-54477-7

Ultrasound Control of Genomic Regulatory Toolboxes for Cancer Immunotherapy

Nat Commun. 2024 Dec 1;15(1):10444. doi: 10.1038/s41467-024-54477-7.

Authors

Yiqian Wu^#^{1

2}, Ziliang Huang^#^{3

4}, Yahan Liu^#⁵, Peixiang He^#³, Yuxuan Wang⁴, Liyanran Yan⁶, Xinhui Wang⁷, Shanzi Gao⁶, Xintao Zhou⁷, Chi Woo Yoon^{3

4}, Kun Sun⁸, Yinglin Situ³, Phuong Ho³, Yushun Zeng⁴, Zhou Yuan^{3

4}, Linshan Zhu^{3

4}, Qifa Zhou⁴, Yunde Zhao⁹, Thomas Liu¹⁰, Gabriel A Kwong¹¹, Shu Chien³, Longwei Liu^{12

13}, Yingxiao Wang^{14

15}

Affiliations

¹ Shu Chien - Gene Lay Department of Bioengineering, Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, USA. yiqianwu@pku.edu.cn.
² National Biomedical Imaging Center, College of Future Technology, Peking University, Beijing, China. yiqianwu@pku.edu.cn.
³ Shu Chien - Gene Lay Department of Bioengineering, Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, USA.
⁴ Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA.
⁵ State Key Laboratory of Vascular Homeostasis and Remodeling, Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
⁶ Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
⁷ National Biomedical Imaging Center, College of Future Technology, Peking University, Beijing, China.
⁸ Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China.
⁹ Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA, USA.
¹⁰ Center for Functional MRI, University of California San Diego, La Jolla, CA, USA.
¹¹ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA, USA.
¹² Shu Chien - Gene Lay Department of Bioengineering, Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, USA. longweil@usc.edu.
¹³ Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA. longweil@usc.edu.
¹⁴ Shu Chien - Gene Lay Department of Bioengineering, Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, USA. ywang283@usc.edu.
¹⁵ Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA. ywang283@usc.edu.

^# Contributed equally.

Abstract

There remains a critical need for the precise control of CRISPR (clustered regularly interspaced short palindromic repeats)-based technologies. Here, we engineer a set of inducible CRISPR-based tools controllable by focused ultrasound (FUS), which can penetrate deep and induce localized hyperthermia for transgene activation. We demonstrate the capabilities of FUS-inducible CRISPR, CRISPR activation (CRISPRa), and CRISPR epigenetic editor (CRISPRee) in modulating the genome and epigenome. We show that FUS-CRISPR-mediated telomere disruption primes solid tumours for chimeric antigen receptor (CAR)-T cell therapy. We further deliver FUS-CRISPR in vivo using adeno-associated viruses (AAVs), followed by FUS-induced telomere disruption and the expression of a clinically validated antigen in a subpopulation of tumour cells, functioning as "training centers" to activate synthetic Notch (synNotch) CAR-T cells to produce CARs against a universal tumour antigen to exterminate neighboring tumour cells. The FUS-CRISPR(a/ee) toolbox hence allows the noninvasive and spatiotemporal control of genomic/epigenomic reprogramming for cancer treatment.

MeSH terms

Animals
CRISPR-Cas Systems*
Cell Line, Tumor
Clustered Regularly Interspaced Short Palindromic Repeats
Dependovirus / genetics
Gene Editing / methods
Genomics / methods
Humans
Immunotherapy / methods
Immunotherapy, Adoptive / methods
Mice
Neoplasms* / genetics
Neoplasms* / immunology
Neoplasms* / therapy
Receptors, Chimeric Antigen* / genetics
Receptors, Chimeric Antigen* / metabolism
Ultrasonic Waves

Substances

Receptors, Chimeric Antigen

Abstract

MeSH terms

Substances

Grants and funding