Transcription factor FOXO1 enhances CAR-T cell anti-cancer activity and prolongs its lifespan

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Transcription factor FOXO1 enhances CAR-T cell anti-cancer activity and prolongs its lifespan

Transcription factor FOXO1 enhances CAR-T cell anti-cancer activity and prolongs its lifespan

T cells are immune cells capable of identifying and killing pathogens to protect the host. Cancer cells can often evade the host’s immune system. CAR-T cell therapy involves genetically engineering a patient’s own T cells to recognize and kill cancer cells. Currently, the FDA has approved multiple CAR-T cell therapies for the treatment of blood cancers such as leukemia and lymphoma.

However, over 50% of cancer patients who respond to CAR-T cell therapy still experience relapse, partly because CAR-T cells often struggle to survive long enough in the patient’s body to completely eliminate tumor cells. Patients who are cured by CAR-T cell therapy typically have longer survival times and more successful battles against cancer cells with their CAR-T cells.

To determine what helps CAR-T cells survive longer, researchers aimed to understand the biological principles behind memory T cells. Memory T cells are naturally occurring T cells designed to persist and maintain function. Previous studies in mice found that the protein FOXO1 promotes the formation of memory T cells, but whether it plays the same role in human T cells or CAR-T cells requires further investigation.

On April 10, 2024, Nature published two back-to-back papers that both confirmed the transcription factor FOXO1 enhances CAR-T cell activity, prevents their exhaustion, and thereby enhances their anti-tumor activity.

Transcription factor FOXO1 enhances CAR-T cell anti-cancer activity and prolongs its lifespan

The first paper from the University of Pennsylvania and Stanford University, titled “FOXO1 is a master regulator of memory programming in CAR T cells,” demonstrated that the transcription factor FOXO1 promotes memory in human CAR-T cells and suppresses their exhaustion, enhancing their anti-tumor activity. The study also found that FOXO1 activity correlates with positive clinical outcomes in patients receiving CAR-T cell therapy or tumor-infiltrating lymphocyte (TIL) therapy.

The research confirmed that overexpression of FOXO1 can increase the anti-tumor activity of human CAR-T cells and emphasized memory reprogramming as a broadly applicable method to optimize the status of therapeutic T cells. This finding could improve the design of CAR-T cell therapy, benefiting more cancer patients.

To further understand the role of FOXO1 in human CAR-T cells, the research team used CRISPR gene editing technology to knock out the FOXO1 gene. They found that in the absence of FOXO1, human CAR-T cells lost the ability to form healthy memory T cells or resist cancer in mouse models, supporting the view that FOXO1 regulates T cell memory and anti-tumor activity.

Next, the research team overexpressed FOXO1 in CAR-T cells, which activated memory-related genes and enhanced the CAR-T cells’ ability to persist and resist cancer in animal models. In contrast, when another memory-promoting factor TCF1 (encoded by the TCF7 gene) was overexpressed, there was no improvement in CAR-T cell activity, suggesting that FOXO1 plays a more unique role in promoting T cell longevity.

Importantly, the research team analyzed patients receiving CAR-T cell therapy or TIL therapy and found that FOXO1 activity correlates with positive clinical outcomes. This underscores the clinical relevance of FOXO1 in cancer immunotherapy.

In summary, this study demonstrates that overexpression of FOXO1 can increase the anti-tumor activity of human CAR-T cell therapy and highlights memory reprogramming as a broadly applicable method to optimize the status of therapeutic T cells.

The research team likened CAR-T cells to light bulbs, which often become exhausted due to fatigue and poor persistence, much like a light bulb running out of power. This study shows that a transcription factor called FOXO1 helps maintain CAR-T cell vitality by activating genes that resist fatigue, promote persistence, and enhance CAR-T cell anti-tumor activity, akin to re-energizing a light bulb.

The second paper from the University of Melbourne, titled “FOXO1 enhances CAR T cell stemness, metabolic fitness, and efficacy,” arrived at the same conclusion through different methods. The team was originally studying the effects of IL-15 on CAR-T cell therapy, as IL-15 has been used in some clinical trials in combination with CAR-T cell therapy. They found that IL-15 helps transform T cells into a stem cell-like state. However, this may also cause CAR-T cells to stall in this state rather than mature to combat cancer.

The team further analyzed the gene expression in CAR-T cells under the influence of IL-15 and found that IL-15 activates FOXO1-related genes. Based on this finding, they modified CAR-T cells to overexpress FOXO1, which made the CAR-T cells more like stem cells but able to mature and fight cancer, and less prone to exhaustion, able to persist longer in mice.

The team stated that validating CAR-T cell therapy with overexpressed FOXO1 in cancer patients might be relatively simple. They have already begun discussions with clinical researchers, and such a clinical trial could start within two years.

Additionally, on April 9, 2024, a team led by Professor Wang Shixuan from Tongji Hospital affiliated with Tongji Medical College of Huazhong University of Science and Technology published a research paper titled “Spatiotemporal transcriptomic changes of human ovarian aging and the regulatory role of FOXP1” in Nature Aging.

The study found that FOXP1 is a core protective factor for ovarian aging, which declines with age. This discovery provides valuable insights into the mechanism of human ovarian aging and potential therapeutic targets.

Links to the papers:

https://www.nature.com/articles/s41586-024-07300-8

https://www.nature.com/articles/s41586-024-07242-1

https://www.nature.com/articles/s43587-024-00607-1