T cell-based cancer immunotherapy has achieved great success in the clinic; however, only a small fraction of patients respond to this therapy. We have investaged the mechanical interactions between immunity and cancer and identify novel strategies to enhance current ACT immunotherapy.
Our results suggest that mechanical stimulation acting on the T cell receptor (TCR) could induce higher levels of proximal signaling and long-term activation compared to static conditions. These results lead to the discovery of a fourth dimension, in addition to the three canonical signals, for T cell activation, the mechanical one. Recapitulating the mechanical interactions present at the interface between the T-cell and the APC can enhance T-cell activation.
Strategies to specifically and safely augment anticancer activity through controlled delivery of T cell supporting factors or drugs for combinatory therapy remain of high interest. Cellular force exerted by cytotoxic T cell upon TCR activation by cognate antigen is a highly specific and instantaneous mechanical stimulus. We therefore exploited the T cell force as a unique biophysical trigger to achieve TCR signalling-responsive drug delivery for enhanced safety and therapeutic outcomes (Mater. Hori. 2020, 7, 3196-3200).
Finally, we have developed stiffening-based immunotherapies for cancer. We showed that T-cell-mediated cancer-cell killing was hampered for cortically soft cancer cells, which have plasma membranes enriched in cholesterol, and that cancer-cell stiffening via cholesterol depletion augments T-cell cytotoxicity and enhances the efficacy of adoptive T-cell therapy against solid tumours in mice (Nat. Biomed. Eng. 2021, 5, 1411-1425). Our findings reveal a mechanical immune checkpoint that could be targeted therapeutically to improve the effectiveness of cancer immunotherapies. We also leveraged the tissue stiffness to engineer next-generation immunotherapies by combining with cytokines, such as IL-10 (Nat. Immunol. 2021, 22, 746–756).
