Stereotactic Radiotherapy Increases Functionally Suppressive Regulatory T Cells in the Tumor Microenvironment

Area of Science:

• Immunology
• Oncology
• Radiotherapy Research

Background:

• Radiotherapy (RT) is known to modulate the immune system, but its specific effects on suppressive immune cells like regulatory T cells (Tregs) within the tumor microenvironment (TME) require further investigation.
• Previous studies suggest increased Treg infiltration post-radiation, yet their functional suppressive capacity remains unclear.

Purpose of the Study:

• To investigate the hypothesis that RT enhances the suppressive function of Tregs in the TME.
• To analyze the phenotypic and functional changes of tumor-infiltrating Tregs (TIL-Tregs) following RT.

Main Methods:

• Utilized the small animal radiation research platform (SARRP) for targeted tumor irradiation, modeling human stereotactic radiotherapy.
• Analyzed tumor-infiltrating lymphocytes (TILs) using flow cytometry and functional assays across multiple tumor models (B16/F10, RENCA, MC38).
• Assessed Treg proliferation and T-cell migration inhibition using Fingolimod, and investigated the role of TGFβ and IL33 signaling.

Main Results:

• RT significantly increased TIL-Treg infiltration, with higher expression of CTLA-4, 4-1BB, and Helios compared to non-irradiated tumors.
• TIL-Tregs from irradiated tumors exhibited equal or enhanced suppressive capacity.
• Tregs demonstrated more robust proliferation than other T-cell subsets post-RT, with expansion likely due to intratumoral proliferation, independent of TGFβ and IL33 signaling.

Conclusions:

• RT increases the number and functional suppressiveness of Tregs in the TME.
• The findings suggest that combining RT with Treg-targeting agents could be a promising strategy to enhance antitumor efficacy.