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

Shaoxian Wu; Jing Jiao; Nuo Wang; Ningning He; You Wu; Hongwei Jiang; Zhang Fang; Rongzhang Chen; Yingting Liu; Yungang Liu; Lujun Chen; Xiao Zheng; Jingting Jiang

doi:10.1016/j.intimp.2024.113330

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

Int Immunopharmacol. 2024 Dec 25;143(Pt 2):113330. doi: 10.1016/j.intimp.2024.113330. Epub 2024 Oct 17.

Authors

Shaoxian Wu¹, Jing Jiao², Nuo Wang¹, Ningning He¹, You Wu¹, Hongwei Jiang¹, Zhang Fang¹, Rongzhang Chen¹, Yingting Liu¹, Yungang Liu³, Lujun Chen⁴, Xiao Zheng⁵, Jingting Jiang⁶

Affiliations

¹ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China.
² Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Nanjing Medical University, Nanjing, Jiangsu 211166, China.
³ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Department of Oncology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213011 Jiangsu, China.
⁴ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: chenlujun@suda.edu.cn.
⁵ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: zhengxiao@suda.edu.cn.
⁶ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China. Electronic address: jiangjingting@suda.edu.cn.

PMID: 39423663
DOI: 10.1016/j.intimp.2024.113330

Abstract

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 ST2⁺Tregs 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 (Foxp3^CreIl1rl1^fl/fl) and evaluated the genetic phenotypes by flow cytometry. A bilateral dorsal tumor-bearing model was established in Foxp3^Cre and Foxp3^CreIl1rl1^fl/fl 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^Cre mice, MWA significantly inhibited the growth of contralateral tumors in Foxp3^CreIl1rl1^fl/fl mice. Its mechanisms include reducing the proportion of Tregs, enhancing the infiltration and effector function of CD8⁺T cells, increasing the proportion of Effector CD8⁺T cells, reducing the proportion of Exhausted CD8⁺T 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.

Keywords: Interleukin-33; Microwave ablation; ST2(+)Tregs; Tumor microenvironment.

MeSH terms

Animals
Cell Line, Tumor
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism
Interleukin-1 Receptor-Like 1 Protein* / genetics
Interleukin-1 Receptor-Like 1 Protein* / metabolism
Interleukin-33* / genetics
Interleukin-33* / metabolism
Lymphocytes, Tumor-Infiltrating* / immunology
Lymphocytes, Tumor-Infiltrating* / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Microwaves* / therapeutic use
Radiofrequency Ablation / methods
T-Lymphocytes, Regulatory* / immunology
Tumor Microenvironment / immunology

Substances

Interleukin-1 Receptor-Like 1 Protein
Il1rl1 protein, mouse
Interleukin-33
Foxp3 protein, mouse
Forkhead Transcription Factors
Il33 protein, mouse