STING agonist cGAMP enhances anti-tumor activity of CAR-NK cells against pancreatic cancer

Yanyan Da; Yuxia Liu; Yuan Hu; Wenzeng Liu; Junpeng Ma; Nan Lu; Chengsheng Zhang; Cai Zhang

doi:10.1080/2162402X.2022.2054105

STING agonist cGAMP enhances anti-tumor activity of CAR-NK cells against pancreatic cancer

Oncoimmunology. 2022 Mar 21;11(1):2054105. doi: 10.1080/2162402X.2022.2054105. eCollection 2022.

Authors

Yanyan Da^{1

2}, Yuxia Liu^{1

3}, Yuan Hu^{1

3}, Wenzeng Liu¹, Junpeng Ma², Nan Lu⁴, Chengsheng Zhang^{2

5}, Cai Zhang^{1

3}

Affiliations

¹ Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China.
² Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
³ Nk CellTech Co., Ltd., Shanghai International Medical Park, Pudong New Area, Shanghai, China.
⁴ Institute of Diagnostics, School of Medicine, Shandong University, Jinan, Shandong, China.
⁵ Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Abstract

Activation of the stimulator of interferon gene (STING)-mediated innate immune response has been suggested as a promising therapeutic strategy for cancers. However, the effects of STING agonist on natural killer (NK) cell-mediated anti-tumor responses in pancreatic cancer remains unknown. Herein, we evaluated the effects of a classical STING agonist cyclic GMP-AMP (cGAMP) on NK cells in pancreatic cancer. We found that cGAMP could directly activate NK cells and enhance the sensitivity of pancreatic cancer cells to NK cell cytotoxicity, suggesting that cGAMP may become a potential adjuvant for NK cell therapy. In addition, combination of CAR-NK-92 cells targeting mesothelin and cGAMP displayed greater antitumor efficacy by inhibiting tumor growth and prolonging survival of the mouse model of pancreatic cancer. These results suggest that the combination of a STING agonist and NK cells may become a novel immunotherapy strategy for pancreatic cancer.

Keywords: CAR-NK-92 cells; STING; STING agonist; cGAMP; pancreatic cancer.

Publication types

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

MeSH terms

Animals
Killer Cells, Natural
Membrane Proteins* / genetics
Mice
Nucleotides, Cyclic / pharmacology
Pancreatic Neoplasms* / therapy

Substances

Membrane Proteins
Nucleotides, Cyclic
cyclic guanosine monophosphate-adenosine monophosphate

Grants and funding

This study is supported in part by the National Natural Science Foundation of China (91842305, 81771686), the Shandong Provincial Key Research and Development Program (Major Scientific and Technological Innovation Project) (Shanxi Provincial Key Research and Development Project 2019JZZY021013), and the Shandong Provincial Natural Science Foundation (Natural Science Foundation of Shandong Province ZR2020MH260), the National Health Commission of People’s Republic of China on the project entitled “Development of scientific system and service platform for cancer precision medicine” (2020-2025), and the operational funds from The First Affiliated Hospital of Xi’an Jiaotong University.