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Contributed by Shu Chien, December 19, 2017 (sent for review August 24, 2017; reviewed by Cheri X. Deng and Sanjay Kumar)
Significance
There is a lack of a general method to noninvasively and remotely manipulate cells with high spatiotemporal precisions. We developed an ultrasound-based mechanogenetics system to achieve this goal. Cells were engineered with the mechanosensor Piezo1 and genetic transducing modules to perceive the mechanical perturbation generated by the ultrasound wave and transduce it into genetic activities. Mechanosensitive and ultrasound-controllable T cells were further engineered to target and eradicate tumor cells with inducible chimeric antigen receptors. This mechanogenetics approach can be extended to remotely control, in principle, any gene activity in live cells for the reprogramming of cellular functions. This method should also provide a general approach to remotely control molecular functions for biological studies and clinical applications, particularly cell-based cancer immunotherapy.
Abstract
While cell-based immunotherapy, especially chimeric antigen receptor (CAR)-expressing T cells, is becoming a paradigm-shifting therapeutic approach for cancer treatment, there is a lack of general methods to remotely and noninvasively regulate genetics in live mammalian cells and animals for cancer immunotherapy within confined local tissue space. To address this limitation, we have identified a mechanically sensitive Piezo1 ion channel (mechanosensor) that is activatable by ultrasound stimulation and integrated it with engineered genetic circuits (genetic transducer) in live HEK293T cells to convert the ultrasound-activated Piezo1 into transcriptional activities. We have further engineered the Jurkat T-cell line and primary T cells (peripheral blood mononuclear cells) to remotely sense the ultrasound wave and transduce it into transcriptional activation for the CAR expression to recognize and eradicate target tumor cells. This approach is modular and can be extended for remote-controlled activation of different cell types with high spatiotemporal precision for therapeutic applications.
Footnotes
- ↵1To whom correspondence may be addressed. Email: kkshung{at}usc.edu, shuchien{at}ucsd.edu, or yiw015{at}eng.ucsd.edu.
Author contributions: Y.P., S.C., and Y. Wang designed research; Y.P., S.Y., J.S., Z.H., C.L., M.A., Y. Wu, and Y.-J.C. performed research; M.S. and K.K.S. contributed new reagents/analytic tools; Y.P. analyzed data; and Y.P., K.K.S., S.C., and Y. Wang wrote the paper.
Reviewers: C.X.D., University of Michigan; and S.K., University of California, Berkeley.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1714900115/-/DCSupplemental.
Published under the PNAS license.
Mechanogenetics for controlled immunotherapy
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