4.8 Article

Selective reprogramming of regulatory T cells in solid tumors can strongly enhance or inhibit tumor growth

Journal

FRONTIERS IN IMMUNOLOGY
Volume 14, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2023.1274199

Keywords

regulatory T cells; folate receptor-delta; tumor immunosuppression; immunomodulation; immunotherapy of cancer

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A specific ligand targeting folate receptor delta has been discovered to effectively target regulatory T cells and inhibit tumor growth, while manipulating the polarization of tumor-infiltrating immune cells.
Folate receptor delta (FR delta) has been used as a biomarker for regulatory T cells (Tregs), because its expression is limited to Tregs and ovum. Although FR delta is unable to bind folate, we have used molecular docking software to identify a folate congener that binds FR delta with high affinity and have exploited this FR delta-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.

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