Researchers at UHN's Princess Margaret Cancer Centre have discovered a promising approach to boost the effectiveness of immunotherapy cancer treatments by manipulating the metabolism of a specific type of immune cell.
Cytotoxic T cells are a type of white blood cells that play a key role in the surveillance and elimination of abnormal cells, including cancerous ones.
Some tumours can evade T cell recognition and attack, which can lead to disease progression. One common strategy in cancer immunotherapy is Adoptive Cell Therapy (ACT), which involves using a patient's own immune cells to fight cancer.
In ACT, immune cells such as T cells are collected from the patient's blood or tumour tissue, modified or activated to enhance their ability to fight tumours, and then infused back into the patient.
"Although successful in some cases, cell therapy typically doesn't offer long-lasting benefits for most patients," explains Dr. Pamela Ohashi, Senior Scientist at Princess Margaret Cancer Centre and senior author of this study. "We aim to improve the way ACT is made to increase its effectiveness long-term."
Previous research indicates that directing interventions towards metabolic stress pathways, which have been conserved through evolution, like nutrient deprivation or energy production, can enhance the ability of T cells to control tumours.
The team set out to study an important molecule that cells produced in response to nutrient starvation, called GCN2 (kinase general control non-depressible 2).
"We knew that when GCN2 is activated, it generally reduces overall protein production, leading to the expression of molecules that coordinate various cellular activities, like protein uptake," explains Dr. Michael St. Paul, Post-Doctoral researcher at Princess Margaret Hospital and first author of this study. "However, the specific role of GCN2 in cytotoxic T cells remains unclear."
To study this, researchers started by investigating amino acid depletion, specifically the lack of arginine, which is recognized for its crucial role in immune cell function.
By moving activated cytotoxic T cells from standard medium to one depleted of arginine, scientists noted an increased activation of GCN2-induced stress response. This was shown by an increase in the production of immune-regulating molecules (cytokines) and enhanced energy production through oxidative metabolism.
To validate these results, they used halofuginone (halo), a GCN2 activator, and observed comparable impacts on T cell function and oxidative metabolism.
"Interestingly, this metabolic shift persisted even after removing the halo from the cells, indicating a sustained change in the metabolism of T cells," explains Dr. Sam Saibil, Staff Oncologist at the Princess Margaret Cancer Centre. "This means that harnessing the intrinsic capabilities of the immune system could lead to more targeted and durable therapeutic interventions."
This study helped understand how GCN2 signaling affects T cell responses to arginine levels, shedding light on potential therapeutic strategies for enhancing immune responses against cancer.
"Our research opens doors to enhancing various forms of cancer immunotherapy by targeting GCN2, signaling a potential paradigm shift in cancer treatment strategies," concludes Dr. Ohashi.
This work was supported by the Canadian Institutes for Health Research Foundation and the Princess Margaret Cancer Foundation.
St Paul M, Saibil SD, Kates M, Han S, Lien SC, Laister RC, Hezaveh K, Kloetgen A, Penny S, Guo T, Garcia-Batres C, Smith LK, Chung DC, Elford AR, Sayad A, Pinto D, Mak TW, Hirano N, McGaha T, Ohashi PS. Ex vivo activation of the GCN2 pathway metabolically reprograms T cells, leading to enhanced adoptive cell therapy. Cell Rep Med. 2024 Mar 19;5(3):101465. doi: 10.1016/j.xcrm.2024.101465.
When cytotoxic T cells identify a cancer cell as dangerous, they release substances that trigger the cancer cell's death, effectively removing the threat while preserving the surrounding healthy tissue.