Tregs ST2 deficiency enhances the abscopal anti-tumor response induced by microwave ablation.

Background: Thermal ablation (TA), including radiofrequency ablation (RFA) and Microwave ablation (MWA) could reduce tumor burden and can stimulate an immune response, but it cannot maintain a lasting immune response. The alarming cytokine IL-33 is constitutively expressed by epithelial cells, endothelial cells, and fibroblasts, but is released during tissue injury to alert the immune system. The presence of ST2Tregs in TME may act as a barrier contributing to this phenomenon.

Methods: In this study, we explored the impact of RFA on the expression of ST2 (also known as IL1RL1) in tumor-infiltrating lymphocytes (TILs). Subsequently, we constructed a Treg cell-specific deletion ST2 mouse model (Foxp3Il1rl1) and evaluated the genetic phenotypes by flow cytometry. A bilateral dorsal tumor-bearing model was established in Foxp3 and Foxp3Il1rl1 mice to explore the anti-tumor effect of MWA. Finally, we used flow cytometry and single-cell transcriptome sequencing (scRNA-seq) to profile CD45 immune cells within TME.

Results: Our findings suggest that ablation upregulates ST2 expression in Tregs within the contralateral TME. Compared with Foxp3 mice, MWA significantly inhibited the growth of contralateral tumors in Foxp3Il1rl1 mice. Its mechanisms include reducing the proportion of Tregs, enhancing the infiltration and effector function of CD8T cells, increasing the proportion of Effector CD8T cells, reducing the proportion of Exhausted CD8T cells, increasing MHC-I molecules in mDC cells and monocytes, and reducing the expression of TAM2 inhibitory molecules and chemokines.

Conclusions: Blocking IL-33/ST2 pathway in Tregs offers a new strategy for MWA in clinical studies of metastatic cancer.