Researchers at MD Anderson Cancer Center have found that RET lung cancers have unusually high levels of a protein called FOXM1, which may make them a strong candidate for a new kind of immune system-based treatment.
Dr. Alexandre Reuben’s group at MD Anderson Cancer Center studied a protein called FOXM1, which is found at very high levels in many cancers, including RET lung cancer. FOXM1 helps cancer cells grow, spread, and survive, and patients whose tumors have high FOXM1 levels typically have worse outcomes. Notably, FOXM1 expression was particularly elevated in tumors harboring RET alterations compared to those expressing other mutations.
The team wanted to investigate whether the immune system could be trained to recognize and attack cells containing FOXM1.
- They identified small pieces of FOXM1 that can be recognized by immune cells called T cells.
- They genetically engineered T cells with special receptors (called TCRs) that allow them to find FOXM1-containing cancer cells.
- In laboratory tests, these engineered T cells (TCR-T cells) were able to specifically recognize and kill cancer cells carrying FOXM1.
- In mice with tumors, treatment with FOXM1-targeted TCR-T cells slowed tumor growth and helped the animals live longer.
This research was supported in part by the Happy Lungs Project (HLP). Find the publication here.
Key Takeaways
Detailed Results From The Study:
FOXM1 Is High in Lung Cancer but Low in Healthy Tissue
Analysis of more than 1,000 lung cancer samples from TCGA revealed significantly elevated FOXM1 expression in both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). In contrast, FOXM1 was generally absent from healthy heart, brain, liver, kidney, and most normal lung samples. Protein analyses confirmed the same pattern, with strong FOXM1 expression in lung cancer and minimal expression in normal tissues.
FOXM1-Derived Targets Are Naturally Presented by Tumor Cells
The team used immunopeptidomics to determine whether FOXM1 fragments are displayed on tumor cell surfaces via HLA molecules, enabling recognition by T cells.
Results showed that two-thirds of tested NSCLC cell lines naturally presented FOXM1-derived epitopes. These epitopes were displayed across multiple HLA types, suggesting broad patient applicability.
This finding confirmed that FOXM1 is not only expressed inside tumors but also visible to the immune system at the tumor cell surface.
Discovery of FOXM1-Specific T Cells
Researchers developed a workflow to identify and isolate T cells capable of recognizing FOXM1-derived peptides. Two particularly promising FOXM1 epitopes were identified:
- YLVPIQFPV (restricted by HLA-A*02:01)
- IYTWIEDHF (restricted by HLA-A*24:02 and HLA-A*23:01)
When healthy donor immune cells were exposed to these peptides, the FOXM1-specific T cell demonstrated potent tumor-killing activity.
These findings confirmed that FOXM1 can generate effective anti-tumor immune responses.
Engineering TCR-T Cells Against FOXM1
The researchers then isolated the most effective FOXM1-reactive T-cell receptors (TCRs) and engineered them into donor T cells, creating FOXM1-targeted TCR-T cells.
Key findings included:
- Robust killing of FOXM1-positive tumor cells.
- Strong production of immune factors such as IFN-γ and MIP-1β.
- Recognition of naturally expressed FOXM1 in cancer cells.
- High sensitivity, detecting low levels of FOXM1 peptides.
Four lead TCR candidates were identified.
Encouraging Safety Profile
One of the biggest challenges in TCR-T therapy is avoiding damage to healthy tissues.
To evaluate this risk, researchers tested FOXM1 TCR-T cells against healthy cell lines derived from lung, liver, heart, kidney and brain.
The engineered T cells showed:
- Minimal cytokine release
- Little to no killing of healthy cells
- Strong preference for FOXM1-expressing tumor cells
These results suggest a low risk of on-target, off-tumor toxicity, though further clinical testing will be required.
FOXM1-Specific Immune Responses Exist in Patients
Importantly, FOXM1-reactive T-cell populations were also identified in patients with NSCLC.
After stimulation, FOXM1-specific T cells expanded dramatically and produced strong immune responses. Analysis of patient tumor samples further revealed TCR signatures closely related to the engineered FOXM1-targeting receptors.
This suggests that naturally occurring anti-FOXM1 immunity may already exist in some patients and can potentially be harnessed therapeutically.
Tumor Control and Survival Benefits in Animal Models
The team tested FOXM1-targeted TCR-T cells in mouse models implanted with FOXM1-positive lung tumors. FOXM1-targeted TCR-T cells significantly reduced tumor growth. Treated animals survived substantially longer than control groups. Engineered T cells persisted in circulation over time. No obvious signs of toxicity were observed.
These in vivo results provide strong proof-of-concept for FOXM1-directed TCR-T therapy.
Conclusion
This study positions FOXM1 as one of the more compelling targets for TCR-T cell therapy in lung cancer. By combining widespread tumor expression, limited normal tissue expression, natural antigen presentation, and strong preclinical efficacy, FOXM1-directed TCR-T cells represent a promising new strategy that could eventually benefit patients with NSCLC including RET patients and other solid tumors.
Dr. Alexandre Reuben
MD Anderson
Dr. Reuben is an Assistant Professor at MD Anderson in the Department of Thoracic/Head & Neck Medical Oncology and the Director of the Immunology Program at the Graduate School of Biomedical Sciences. He is also a member of our Scientific Advisory Board.
