C-C chemokine receptor 4 is a candidate for regulatory T-cell-depletion immunotherapy in differentiated thyroid...

Immunotherapy using immune checkpoint inhibitors is a standard treatment option for many types of malignancies but is not effective for differentiated thyroid cancer (DTC). Regulatory T-cells (Tregs), which are one of the main suppressive factors in the tumor microenvironment, are another important target for immunotherapy. This study investigated the characteristics of Tregs in DTC with the aim of further developing immunotherapy.

Peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs) were obtained from 12 patients with DTC and 12 patients with goiter (benign control group) who underwent primary surgery between February 2017 and September 2022. Flow cytometry analyses were performed for CD4, CD45RA, FOXP3, CC chemokine receptor 4 (CCR4; a candidate Treg-targeting molecule), and immune checkpoint molecules in order to characterize the features of Tregs.

In the DTC patients, age ranged from 39 to 84 years, and the male:female ratio was 7:5. Pathological staging was pT1 or pT2 in 4 patients, pT3 in 8, pN0 in 5, and pN1 in 7, and extrathyroidal extension was observed in 5 patients. Effector Treg (eTreg) frequency in CD4⁺T-cells in TILs and PBLs was significantly higher in DTC than in goiter. Extrathyroidal extension was associated with a higher eTreg frequency in TILs. A positive correlation was found between eTreg frequency and the expression of immune checkpoint molecules (PD-1, TIM3, GITR, and OX40) on eTregs in TILs from DTC patients. These findings suggest that Tregs are activated in DTC and are important in the creation of an immunosuppressive microenvironment. In addition, the mean positive rate (±standard deviation) of CCR4 on eTregs was high in PBLs (95.8 % ± 3.8 %) and TILs (92.8 % ± 9.8 %) from DTC patients, suggesting that CCR4 is a potential target for eTreg-depletion immunotherapy for DTC.

Tregs were increased and activated in DTC tumor tissue, indicating that they play an important role in creating an immunosuppressive microenvironment in DTC. The results suggest that eTreg-depletion immunotherapy using an anti-CCR4 antibody (mogamulizumab) might be effective for treating DTC.