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Published on: November 11, 2016
Selective reprogramming of regulatory T cells in solid tumors can strongly enhance or inhibit tumor growth
Rami Alfar1, John V Napoleon1, Imrul Shahriar1
1Department of Chemistry, Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN, United States.
Abstract:
Folate receptor delta (FRδ) has been used as a biomarker for regulatory T cells (Tregs), because its expression is limited to Tregs and ovum. Although FRδ is unable to bind folate, we have used molecular docking software to identify a folate congener that binds FRδ with high affinity and have exploited this FRδ-specific ligand to target attached drugs (imaging agents, immune activators, and immune suppressors) specifically to Tregs in murine tumor xenografts. Analysis of treated tumors demonstrates that targeting of a Toll-like receptor 7 agonist inhibits Treg expression of FOXP3, PD-1, CTLA4, and HELIOS, resulting in 40-80% reduction in tumor growth and repolarization of other tumor-infiltrating immune cells to more inflammatory phenotypes. Targeting of the immunosuppressive drug dexamethasone, in contrast, promotes enhanced tumor growth and shifts the tumor-infiltrating immune cells to more anti-inflammatory phenotypes. Since Tregs comprise <1% of cells in the tumor masses examined, and since the targeted drugs are not internalized by cancer cells, these data demonstrate that Tregs exert a disproportionately large effect on tumor growth. Because the targeted drug did not bind to Tregs or other immune cells in healthy tissues, the data demonstrate that the immunosuppressive properties of Tregs in tumors can be manipulated without causing systemic toxicities associated with global reprogramming of the immune system.
Insights
Researchers targeted regulatory T cells (Tregs) using a novel folate-binding ligand. This approach selectively delivered drugs to Tregs in tumors, significantly reducing tumor growth and altering immune cell phenotypes without systemic toxicity.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Folate receptor delta (FRδ) is a biomarker for regulatory T cells (Tregs), though it does not bind folate.
- Targeting Tregs within the tumor microenvironment is a promising strategy for cancer immunotherapy.
- Existing methods for immune modulation often lead to systemic toxicities.
Purpose of the Study:
- To identify a high-affinity folate congener that binds to FRδ.
- To utilize this FRδ-specific ligand for targeted delivery of therapeutic agents to Tregs in murine tumor models.
- To evaluate the impact of targeted Treg modulation on tumor growth and immune cell infiltration.
Main Methods:
- Molecular docking was employed to identify a folate congener with high affinity for FRδ.
- The FRδ-specific ligand was conjugated to therapeutic agents (Toll-like receptor 7 agonist, dexamethasone).
- Targeted drug delivery to Tregs in murine tumor xenografts was assessed, followed by analysis of tumor growth and immune cell phenotypes.
Main Results:
- Targeting a Toll-like receptor 7 agonist to Tregs inhibited Treg markers (FOXP3, PD-1, CTLA4, HELIOS), reduced tumor growth by 40-80%, and promoted inflammatory immune cell phenotypes.
- Targeting dexamethasone to Tregs enhanced tumor growth and shifted immune cells towards anti-inflammatory phenotypes.
- Targeted drugs did not bind to Tregs or immune cells in healthy tissues, indicating a lack of systemic toxicity.
Conclusions:
- Tregs exert a significant influence on tumor growth, even at low frequencies (<1%).
- Targeted delivery of immunomodulatory drugs to Tregs in tumors can effectively manipulate Treg function.
- This FRδ-targeted approach offers a strategy for cancer therapy with reduced systemic side effects.
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