Selective Reprogramming of Regulatory T Cells in Solid Tumors Can Strongly Enhance or Inhibit Tumor Growth

Authors

Rami Alfar
John V Napoleon
Imrul Shahriar
Richard Finnell
Cole Walchle
Austin Johnson
Philip S Low

Publication Date

1-1-2023

Journal

Frontiers in Immunology

DOI

10.3389/fimmu.2023.1274199

PMID

37928524

PMCID

PMC10623129

PubMedCentral® Posted Date

10-20-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Animals, Mice, T-Lymphocytes, Regulatory, Molecular Docking Simulation, Neoplasms, Transcription Factors, Immunosuppressive Agents, Folic Acid, regulatory T cells, folate receptor-delta, tumor immunosuppression, immunomodulation, immunotherapy of cancer

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

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