Investigators have discovered a method to significantly enhance T cells by providing them with additional mitochondria from multipotent stromal cells.
Battling cancer takes a toll on T cells. Adverse tumor environments can deplete their mitochondrial function, resulting in a state known as T cell exhaustion. This issue also complicates adoptive cell therapies, which involve infusing healthy, cancer-targeting T cells into patients. A new approach is essential to boost mitochondrial performance and recharge T cells.
Researchers from Brigham and Women’s Hospital, part of the Mass General Brigham healthcare system, along with partners at the Leibniz Institute for Immunotherapy in Germany, have created a technique to “supercharge” T cells by infusing them with additional mitochondria from multipotent stromal cells. A study detailed in Cell reveals that these enhanced T cells demonstrate improved anti-tumor activity and show fewer signs of exhaustion in preclinical cancer models, indicating that this method might advance current immunotherapies.
“These enhanced T cells break through a key obstacle of immunotherapy by infiltrating the tumor and overcoming the immune-resistant environment within,” stated Shiladitya Sengupta, PhD, a main author and member of the Brigham’s Department of Medicine. “Mitochondria supply the energy needed. It’s as if we’re filling up T cells at a gas station. This transfer of mitochondria represents the beginning of organellar therapy, where we deliver organelles to cells to improve their effectiveness.”
“Previous attempts to boost mitochondrial performance in T cells concentrated on specific genes or pathways, but these approaches do not succeed when mitochondria are already damaged or dysfunctional. Our method involves transferring whole, healthy mitochondria organelles into the cells. This process is similar to organ transplants conducted at a microscopic scale,” explained Luca Gattinoni, MD, co-leading author of the study.
To develop this technique, the team built on earlier findings indicating that cancer cells can absorb mitochondria from immune cells through intercellular nanotubes, which the researchers referred to as “tiny tentacles.” Collaborating with scientists at the Leibniz Institute, they explored the interactions between bone marrow stromal cells (BMSCs) and cytotoxic T cells. Using various microscopy methods, they observed that BMSCs extended nanotubes to activated T cells, transferring intact mitochondria. This process rejuvenated the T cells (mito+), which then displayed increased respiratory abilities, indicating enhanced metabolism.
The research group analyzed the impact of supercharging T cells on their immune function. When infused into a mouse model of melanoma, mito+ cells exhibited significantly stronger anti-tumor reactions and improved survival rates compared to T cells that did not receive additional mitochondria. Additional tests revealed that mito+ cells could penetrate tumors efficiently, proliferate quickly, and pass their additional mitochondria to their offspring, which remained in the cells long-term. Moreover, the study found that mito+ cells could endure and resist T cell exhaustion within the challenging tumor environment.
The researchers observed that supercharging human T cells aided the immune system in combatting tumors across various cancer models. Notably, tumor-infiltrating lymphocytes and CAR-T cells, which frequently develop damaged mitochondria in the tumor environment, exhibited enhanced tumor-fighting capabilities when boosted with mitochondria from primary BMSCs sourced from human donors.
The authors propose that future uses could involve employing patient-specific BMSCs to enhance T cells for adoptive transfer.
