LAG3 blockade coordinates with microwave ablation to promote CD8+ T cell-mediated anti-tumor immunity

Dong Shao; Yaping Chen; Hao Huang; Yingting Liu; Junjun Chen; Dawei Zhu; Xiao Zheng; Lujun Chen; Jingting Jiang

doi:10.1186/s12967-022-03646-7

LAG3 blockade coordinates with microwave ablation to promote CD8⁺ T cell-mediated anti-tumor immunity

J Transl Med. 2022 Sep 30;20(1):433. doi: 10.1186/s12967-022-03646-7.

Authors

Dong Shao^#^{1

2

3

4}, Yaping Chen^#^{1

2

3}, Hao Huang^{1

2

3}, Yingting Liu^{1

2

3

5}, Junjun Chen^{1

2

3}, Dawei Zhu^{1

2

3}, Xiao Zheng^{1

2

3}, Lujun Chen^{6

7

8}, Jingting Jiang^{9

10

11

12}

Affiliations

¹ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China.
² Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
³ Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
⁴ Department of Gastroenterology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
⁵ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, Jiangsu, People's Republic of China.
⁶ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China. chenlujun@suda.edu.cn.
⁷ Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China. chenlujun@suda.edu.cn.
⁸ Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China. chenlujun@suda.edu.cn.
⁹ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China. Jiangjingting@suda.edu.cn.
¹⁰ Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China. Jiangjingting@suda.edu.cn.
¹¹ Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China. Jiangjingting@suda.edu.cn.
¹² State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, Jiangsu, People's Republic of China. Jiangjingting@suda.edu.cn.

^# Contributed equally.

Abstract

Background: The immune checkpoint inhibitors (ICIs) combined with other therapeutic strategies have shown exciting results in various malignancies, and ICIs have now become the gold standard for current cancer treatment. In several preclinical and clinical investigations, ablation coupled with immunotherapy has proved to be quite effective. Our previous studies have shown that ablation coupled with ICI is a potential anti-cancer regimen for colorectal cancer liver metastases (CRLM). Furthermore, we have reported that following microwave ablation (MWA), the expression of LAG3 is up-regulated in tumor microenvironment (TME), indicating that LAG3 is implicated in the regulation of immunosuppressive immune response, and combination therapy of MWA and LAG3 blockade can serve as a promising therapeutic strategy against cancer.

Methods: The expression of LAG3 was investigated in this study utilizing a preclinical mouse model treated with MWA. Moreover, we monitored the tumor development and survival in mice to assess the anti-cancer effects of MWA alone or in combination with LAG3 blockade. Flow cytometry was also used to phenotype the tumor-infiltrating lymphocytes (TILs) and CD8⁺ T cell effector molecules. We finally analyzed the single-cell RNA sequencing (scRNA-seq) data of infiltrating CD45⁺ immune cells in the tumors from the MWA alone and MWA combined with LAG3 blockade groups.

Results: After MWA, the expression of LAG3 was up-regulated on sub-populations of TILs, and introducing LAG3 blockade to MWA postponed tumor development and extended survival in the MC38 tumor model. Flow cytometry and scRNA-seq revealed that LAG3 blockade in combination with MWA markedly boosted the proliferation and the function of CD8⁺ TILs, leading to altered myeloid cells in the TME.

Conclusion: Combination therapy of LAG3 blockade and MWA was a unique therapeutic regimen for some solid tumors, and such combination therapy might reprogram the TME to an anti-tumor manner.

Keywords: Combinational immunotherapy; Immune checkpoint inhibitors; LAG3; Microwave ablation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes
Immune Checkpoint Inhibitors
Liver Neoplasms*
Lymphocytes, Tumor-Infiltrating
Mice
Microwaves* / therapeutic use
Tumor Microenvironment

Substances

Immune Checkpoint Inhibitors