Periodic Reporting for period 4 - MechanoIMM (Mechanical Immunoengineering for Enhanced T-cell Immunotherapy)
Berichtszeitraum: 2023-06-01 bis 2023-11-30
Cancer is one of the leading causes of death worldwide, accounting for nearly 10 million deaths in 2020. Cancer immunotherapy is a type of cancer treatment that harnesses the power of a patient’s immune system to fight cancer, which is transforming the standard-of-care. Among a variety of forms of cancer immunotherapy, adoptive T-cell transfer (ACT) is a potent one that relies on direct infusion of a large number of tumour-reactive T cells or other immune cells into patients. ACT therapy, such as CAR T-cell therapy, has elicited striking clinical responses in blood cancers. However, solid tumour remains a major challenge as tumour employs a number of strategies to prevent the tumour reactive T cells from reaching the tumour sites and attacking cancer cells by generating a highly immunosuppressive microenvironment.
To further enhance ACT immunotherapy and expand its applications to solid tumours, scientists have been focusing on modulating the biochemical interactions between immunity and cancer. However, there are extensive mechanical interactions that regulate immune responses but are largely underappreciated. MechanoIMM has demonstrated several innovative mechanical immunoengineering strategies through manipulating biophysical interactions to enhance the efficacy and safety of ACT therapy for cancer.
This proposed project opens a new horizon for immunoengineering through biomechanical modulation of immunity for enhanced cancer immunotherapy and provides novel insight into the fundamentals of mechanotransduction in immune system in health and disease.
To further enhance ACT immunotherapy and expand its applications to solid tumours, scientists have been focusing on modulating the biochemical interactions between immunity and cancer. However, there are extensive mechanical interactions that regulate immune responses but are largely underappreciated. MechanoIMM has demonstrated several innovative mechanical immunoengineering strategies through manipulating biophysical interactions to enhance the efficacy and safety of ACT therapy for cancer.
This proposed project opens a new horizon for immunoengineering through biomechanical modulation of immunity for enhanced cancer immunotherapy and provides novel insight into the fundamentals of mechanotransduction in immune system in health and disease.
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).
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).
We have demonstrated, for the first time, a T cell force-responsive delivery system for anticancer drugs. Our results show that this cellular force-responsive system specifically released anticancer drugs in a T cell force-dependent manner and significantly enhanced cancer cell killing in vitro and in vivo. This work opens a new horizon toward designing next-generation drug delivery systems in response to signalling-specific cellular forces.
Our findings reveal a mechanical immune checkpoint that could be targeted therapeutically to improve the effectiveness of cancer immunotherapies. For the first time, we demonstrated a new type immune checkpoint, named “mechanical immune checkpoint”, which is distinct from any known immune checkpoints that are all biochemistry-based. In addition, we demonstrated, for the first time, a T cell force-responsive delivery system for anticancer drugs. This work opens a new horizon toward designing next-generation drug delivery systems in response to signalling-specific cellular forces. We also identified a new way to boost ACT immunotherapy using engineered interleukin-10–Fc fusion protein.
Our findings reveal a mechanical immune checkpoint that could be targeted therapeutically to improve the effectiveness of cancer immunotherapies. For the first time, we demonstrated a new type immune checkpoint, named “mechanical immune checkpoint”, which is distinct from any known immune checkpoints that are all biochemistry-based. In addition, we demonstrated, for the first time, a T cell force-responsive delivery system for anticancer drugs. This work opens a new horizon toward designing next-generation drug delivery systems in response to signalling-specific cellular forces. We also identified a new way to boost ACT immunotherapy using engineered interleukin-10–Fc fusion protein.