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Neutralization of TGFβ Improves Tumor Immunity and Reduces Tumor Progression in Ovarian Carcinoma
Brandon M Roane1, Selene Meza-Perez2, Ashwini A Katre1
1Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama.
Abstract:
The immunosuppressive effects of TGFβ promotes tumor progression and diminishes response to therapy. In this study, we used ID8-p53-/- tumors as a murine model of high-grade serous ovarian cancer. An mAb targeting all three TGFβ ligands was used to neutralize TGFβ. Ascites and omentum were collected and changes in T-cell response were measured using flow. Treatment with anti-TGFβ therapy every other day following injection of tumor cells resulted in decreased ascites volume (4.1 mL vs. 0.7 mL; P < 0.001) and improved the CD8:Treg ratio (0.37 vs. 2.5; P = 0.02) compared with untreated mice. A single dose of therapy prior to tumor challenge resulted in a similar reduction of ascites volume (2.7 vs. 0.67 mL; P = 0.002) and increased CD8:Tregs ratio (0.36 vs. 1.49; P = 0.007), while also significantly reducing omental weight (114.9 mg vs. 93.4 mg; P = 0.017). Beginning treatment before inoculation with tumor cells and continuing for 6 weeks, we observe similar changes and prolonged overall survival (median 70 days vs. 57.5 days). TGFβ neutralization results in favorable changes to the T-cell response within the tumor microenvironment, leading to decreased tumor progression in ovarian cancer. The utilization of anti-TGFβ therapy may be an option for management in patients with ovarian cancer to improve clinical outcomes and warrants further investigation.
Insights
Neutralizing TGFβ (transforming growth factor beta) in ovarian cancer models reduced ascites and improved T-cell responses. This therapy shows promise for enhancing treatment outcomes in ovarian cancer patients.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Transforming growth factor beta (TGFβ) exhibits immunosuppressive properties that can accelerate tumor progression and reduce treatment efficacy.
- High-grade serous ovarian cancer is characterized by an immunosuppressive tumor microenvironment, often driven by TGFβ signaling.
Purpose of the Study:
- To investigate the therapeutic potential of neutralizing TGFβ in a murine model of high-grade serous ovarian cancer.
- To evaluate the impact of anti-TGFβ therapy on tumor progression, ascites formation, and T-cell responses within the tumor microenvironment.
Main Methods:
- Utilized ID8-p53-/- tumors as a murine model for high-grade serous ovarian cancer.
- Administered a monoclonal antibody (mAb) targeting all three TGFβ ligands to neutralize TGFβ activity.
- Assessed changes in T-cell populations (CD8:Treg ratio) in ascites and omentum via flow cytometry.
- Monitored ascites volume, omental weight, and overall survival in treated versus untreated mice.
Main Results:
- Treatment with anti-TGFβ therapy significantly decreased ascites volume and improved the CD8:Treg ratio, indicating a more favorable anti-tumor T-cell response.
- A single dose of anti-TGFβ therapy prior to tumor challenge also reduced ascites and omental weight, enhancing the CD8:Treg ratio.
- Prophylactic and continuous anti-TGFβ treatment led to prolonged overall survival in the ovarian cancer model.
Conclusions:
- TGFβ neutralization effectively modulates the tumor microenvironment, promoting anti-tumor T-cell responses and inhibiting tumor progression in ovarian cancer.
- Anti-TGFβ therapy represents a potential therapeutic strategy for ovarian cancer, warranting further clinical investigation to improve patient outcomes.
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