- KAIST and Seoul St. Mary's Hospital identify how ATRA prevents terminal exhaustion of immune cells

- Compound found to preserve cancer-fighting ability of CD8 T cells, enhance anti-PD-1 therapy

KAIST Professor Lee Heung-kyu (left) and postdoctoral researcher Kang In, who conducted the research. [Provided by KAIST]
KAIST Professor Lee Heung-kyu (left) and postdoctoral researcher Kang In, who conducted the research. [Provided by KAIST]

Researchers have identified a new potential approach to improving the effectiveness of immune-based treatments for glioblastoma, one of the most aggressive and treatment-resistant brain tumors.

KAIST announced Tuesday that a research team led by Professor Lee Heung-kyu of the Department of Biological Sciences, working with collaborators at Seoul St. Mary's Hospital and Konyang University College of Medicine, has found that all-trans retinoic acid (ATRA) — an active metabolite of vitamin A — can suppress the terminal exhaustion of CD8 T cells within brain tumors and enhance the effectiveness of the anticancer drug anti-PD-1.

Glioblastoma is a notoriously difficult-to-treat brain tumor that frequently recurs even after surgery, radiation and chemotherapy. Immunotherapy has also shown limited results. A key reason is "immune cell exhaustion," in which immune cells that infiltrate the tumor gradually lose their ability to attack cancer cells after prolonged exposure.

When CD8 T cells — which directly attack cancer cells — fall into terminal exhaustion, their cancer-killing capacity drops sharply. At that stage, even anti-PD-1 treatment, which works by releasing a kind of "brake" that cancer cells apply to immune cells, struggles to produce meaningful results.

Rather than trying to revive already-exhausted immune cells, the research team focused on preventing them from becoming fully depleted in the first place. Their answer was ATRA, a compound derived from vitamin A.

When the team recreated the oxygen-deprived, tumor-rich environment of a brain tumor in the laboratory, CD8 T cells exposed to ATRA showed a significantly lower rate of progression to terminal exhaustion.

Their cancer-fighting capacity was also preserved. T cells treated with ATRA produced higher levels of immune signaling molecules needed to attack cancer cells, including interleukin-2 (IL-2), interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α).

A schematic diagram of the research findings (AI-generated image). [Provided by KAIST]
A schematic diagram of the research findings (AI-generated image). [Provided by KAIST]

The effects were also observed in a mouse brain tumor model. Administering ATRA increased both the number and function of CD8 T cells within tumors, reduced tumor burden and extended survival.

In recurrent brain tumors particularly, anti-PD-1 alone produced limited results, but combining it with ATRA significantly improved tumor suppression and long-term survival outcomes.

The findings were further supported by human patient data. Patients with higher expression of retinoic acid response-related genes tended to show lower levels of immune cell exhaustion and better survival outcomes.

However, this research was not a clinical trial demonstrating ATRA's therapeutic effects in actual patients. Further studies will be needed to confirm the optimal delivery method, appropriate dosage and combined effects with immunotherapy before it can be applied in clinical settings.

"The recurrent brain tumor model introduced in this research could serve as a useful animal model for validating other brain tumor treatment approaches in the future," Lee said. "By using this recurrent brain tumor model in subsequent drug validation and immunotherapy efficacy studies, we can pursue results that are closer to clinical reality."

The findings were published in the international journal Signal Transduction and Targeted Therapy on Aug. 26.


nbgkoo@heraldcorp.com