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Identifying and reprogramming softness-driven cancer stem-like cells overcomes CAR-T cell resistance in solid

Yunjia Qu^1,2, Yuxuan Wang¹, Linshan Zhu¹

¹Alfred E. Mann Department of Biomedical Engineering, Department of Quantitative Computational Biology, Department of Stem Cell and Regenerative Medicine, University of Southern California, Los Angeles, CA, USA.

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Summary

Cancer cells on soft surfaces resist T cell therapy by activating stem-like programs. A novel mechano-recorder identified these cells, enabling a reprogrammer to make them targetable, improving cancer cell elimination.

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Area of Science:

Biomedical Engineering
Cancer Biology
Immunology

Background:

Solid tumors exhibit significant mechanical heterogeneity.
The impact of mechanical cues on cancer cell susceptibility to T cell-based therapies is not fully understood.
Cancer cells on soft matrices show reduced sensitivity to chimeric antigen receptor T cell cytotoxicity.

Purpose of the Study:

To investigate the mechanisms by which mechanical softness influences cancer cell resistance to T cell therapy.
To identify and characterize cancer cells that respond to mechanical softness.
To develop a strategy to overcome mechanobiological resistance in cancer cells.

Main Methods:

Engineered a doxycycline-gated, calcium-activated transcriptional mechano-recorder to track past mechanosensing activity.
Utilized transcriptomic analyses to profile recorder-positive cells.
Rewired the mechano-recorder into a mechano-reprogrammer by expressing CD19.
Tested the efficacy of the mechano-reprogrammer in vitro and in animal models.

Main Results:

Soft matrices induce elevated extracellular adenosine triphosphate and sustained calcium activity in cancer cells.
Mechano-recorder identified cells exhibiting a stem-like program, including epithelial-mesenchymal transition and elevated stemness markers.
Rewired mechano-reprogrammer enabled CD19-directed T cells to target and eliminate softness-responsive, stem-like cancer cells.
Improved elimination of resistant cancer cells in culture and animal models.

Conclusions:

Mechanical softness confers resistance to T cell therapy by promoting a stem-like cancer cell phenotype.
A novel mechano-recorder can identify and profile mechanosensitive cancer cells.
A mechano-reprogrammer strategy converts mechanobiological resistance into therapeutic vulnerability, enhancing cancer cell elimination.