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Updated: Jan 10, 2026
DNA Tension Probes to Map the Transient Piconewton Receptor Forces by Immune Cells
Published on: March 20, 2021
Chimeric Antigen Receptors Transmit Piconewton Forces that are Coupled with T Cell Function
Abstract:
Chimeric antigen receptor (CAR) T cells are engineered to display a receptor that binds antigens expressed on the surface of cancerous cells, which leads to cancer cytotoxicity. Recently, the T cell field has come to recognize the role of small, piconewton level forces in establishing specificity and cytotoxicity in naïve T cells with the αβ TCR, raising the possibility that these forces could be present in CAR T cells. Using DNA-based tension probes, we reveal 8-19 pN mechanical forces with ∼1 sec timescales transmitted by CAR T cells to their target antigens. CAR-antigen force magnitude is independent of CAR expression level and shows heterogeneity across different T cell donors, suggesting utility as a biomarker of T cell fitness. Using an established exhaustion model, we show strong correlation between CAR exhaustion, cytotoxic capacity, and CAR-antigen force, suggesting that CAR mechanics provide a biomarker of CAR potency complementary to functional assays. Pharmacological inhibition studies demonstrate that CAR forces are driven by actin, Zap70 and Src family proximal kinases. Titration of dasatinib, a clinically used tyrosine kinase inhibitor also dampens both CAR-antigen tension and CAR function in a dose-dependent manner. Structural engineering of the CAR confirms that force levels are modulated by the scFv receptor and co-stimulatory domains, but force transmission requires CD3ζ ITAMs. Taken together, this work shows that CAR T cells transmit pN force to their cognate antigens which holds potential significance in the design and screening of CAR therapeutic candidates and for predicting treatment outcomes in a personalized fashion.
Insights
Chimeric antigen receptor (CAR) T cells transmit piconewton (pN) forces to target cancer cells. This CAR-antigen mechanical force can serve as a biomarker for T cell fitness and predict treatment outcomes.
Area of Science:
- Immunology
- Biophysics
- Cancer Therapy
Background:
- Chimeric antigen receptor (CAR) T cells are engineered for cancer immunotherapy.
- The role of piconewton (pN) forces in T cell receptor (TCR) function is increasingly recognized.
- The presence and significance of mechanical forces in CAR T cell interactions remain largely unexplored.
Purpose of the Study:
- To investigate the mechanical forces transmitted by CAR T cells to their target antigens.
- To explore the potential of CAR-antigen forces as biomarkers for T cell potency and fitness.
- To elucidate the molecular mechanisms underlying CAR T cell force generation and transmission.
Main Methods:
- Utilized DNA-based tension probes to measure forces between CAR T cells and target antigens.
- Employed an established CAR T cell exhaustion model to correlate force with cytotoxic capacity.
- Conducted pharmacological inhibition studies targeting key signaling molecules (actin, Zap70, Src kinases).
- Performed structural engineering of CAR components to assess their impact on force transmission.
Main Results:
- CAR T cells transmit 8-19 pN forces to target antigens on a timescale of ~1 second.
- CAR-antigen force magnitude is independent of CAR expression level but shows donor heterogeneity.
- CAR-antigen force strongly correlates with CAR exhaustion and cytotoxic capacity.
- CAR forces are dependent on actin, Zap70, Src family kinases, and CD3ζ ITAMs.
- Dasatinib, a tyrosine kinase inhibitor, dose-dependently reduces both CAR-antigen force and function.
Conclusions:
- CAR T cells actively transmit piconewton forces to their cognate antigens.
- CAR-antigen mechanical force is a potential biomarker for T cell fitness, potency, and exhaustion.
- Understanding CAR mechanics offers insights into CAR T cell design and personalized treatment strategies.
- These findings highlight the significance of mechanical forces in CAR T cell-mediated immunotherapy.
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