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Updated: Dec 11, 2025
An Orthotopic Model of Serous Ovarian Cancer in Immunocompetent Mice for in vivo Tumor Imaging and Monitoring of Tumor Immune Responses
Published on: November 28, 2010
Ovarian granulosa cell tumor characterization identifies FOXL2 as an immunotherapeutic target
Stefano Pierini1,2, Janos L Tanyi2, Fiona Simpkins2
1Department of Radiation Oncology and.
Abstract:
Granulosa cell tumors (GCT) are rare ovarian malignancies. Due to the lack of effective treatment in late relapse, there is a clear unmet need for novel therapies. Forkhead Box L2 (FOXL2) is a protein mainly expressed in granulosa cells (GC) and therefore is a rational therapeutic target. Since we identified tumor infiltrating lymphocytes (TILs) as the main immune population within GCT, TILs from 11 GCT patients were expanded, and their phenotypes were interrogated to determine that T cells acquired late antigen-experienced phenotypes and lower levels of PD1 expression. Importantly, TILs maintained their functionality after ex vivo expansion as they vigorously reacted against autologous tumors (100% of patients) and against FOXL2 peptides (57.1% of patients). To validate the relevance of FOXL2 as a target for immune therapy, we developed a plasmid DNA vaccine (FoxL2-tetanus toxin; FoxL2-TT) by fusing Foxl2 cDNA with the immune-enhancing domain of TT. Mice immunization with FoxL2-TT controlled growth of FOXL2-expressing ovarian (BR5) and breast (4T1) cancers in a T cell-mediated manner. Combination of anti-PD-L1 with FoxL2-TT vaccination further reduced tumor progression and improved mouse survival without affecting the female reproductive system and pregnancy. Together, our results suggest that FOXL2 immune targeting can produce substantial long-term clinical benefits. Our study can serve as a foundation for trials testing immunotherapeutic approaches in patients with ovarian GCT.
Insights
Targeting Forkhead Box L2 (FOXL2) with novel immunotherapies shows promise for rare granulosa cell tumors (GCT). T cells from GCT patients effectively target tumors and FOXL2, suggesting a new treatment avenue.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Granulosa cell tumors (GCT) are rare ovarian cancers with limited late-stage treatment options.
- Forkhead Box L2 (FOXL2) is a key protein expressed in GCT, making it a potential therapeutic target.
- Tumor-infiltrating lymphocytes (TILs) are the primary immune cells within GCT.
Purpose of the Study:
- To investigate the therapeutic potential of targeting FOXL2 in GCT.
- To evaluate the functionality of TILs from GCT patients.
- To develop and test a novel DNA vaccine targeting FOXL2.
Main Methods:
- Expansion and phenotypic analysis of TILs from 11 GCT patients.
- Ex vivo testing of TILs against autologous tumors and FOXL2 peptides.
- Development of a plasmid DNA vaccine (FoxL2-TT) by fusing FOXL2 cDNA with tetanus toxin.
- In vivo efficacy studies of FoxL2-TT vaccination in mice, alone and in combination with anti-PD-L1 therapy.
Main Results:
- TILs exhibited late antigen-experienced phenotypes with reduced PD1 expression.
- Expanded TILs demonstrated robust anti-tumor activity against autologous GCT and FOXL2 peptides.
- FoxL2-TT vaccination controlled FOXL2-expressing tumor growth in mice via T cell-mediated immunity.
- Combination therapy with anti-PD-L1 and FoxL2-TT significantly reduced tumor progression and improved survival.
Conclusions:
- FOXL2 is a viable target for GCT immunotherapy.
- Ex vivo expanded TILs retain anti-tumor functionality.
- FOXL2-based vaccination, particularly combined with immune checkpoint blockade, offers a promising strategy for GCT treatment.
- This research provides a foundation for clinical trials of immunotherapeutic approaches in ovarian GCT.
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