期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 24, 页码 13730-13739出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1919690117
关键词
STING; DMXAA; Merkel cell carcinoma; gene therapy; antitumor immune response
资金
- NIH [R01CA187718, R21AR074073, R21AI149761, T32CA009140, U19AI117950]
- National Cancer Institute Cancer Center Support Grant [NCI P30 CA016520]
- Penn Center for AIDS Research Pilot Award [P30 AI 045008]
- Human Immunology Core [P30-CA016520, P30AI045008]
Merkel cell carcinoma (MCC) is a lethal skin cancer that metastasizes rapidly. Few effective treatments are available for patients with metastatic MCC. Poor intratumoral T cell infiltration and activation are major barriers that prevent MCC eradication by the immune system. However, the mechanisms that drive the immunologically restrictive tumor microenvironment remain poorly understood. In this study, we discovered that the innate immune regulator stimulator of IFN genes (STING) is completely silenced in MCCs. To reactivate STING in MCC, we developed an application of a human STING mutant, STING(S162A/G230I/Q266I), which we found to be readily stimulated by a mouse STING agonist, DMXAA. This STING molecule was efficiently delivered toMCC cells via an AAV vector. Introducing STING(S162A/G230I/Q266I) expression and stimulating its activity by DMXAA in MCC cells reactivates their antitumor inflammatory cytokine/chemokine production. In response to MCC cells with restored STING, cocultured T cells expressing MCPyV-specific T cell receptors (TCRs) showincreased cytokine production, migration toward tumor cells, and tumor cell killing. Our study therefore suggests that STING deficiency contributes to the immune suppressive nature of MCCs. More importantly, DMXAA stimulation of STING(S162A/G230I/Q266I) causes robust cell death in MCCs as well as several other STING-silenced cancers. Because tumor antigens and DNA released by dying cancer cells have the potential to amplify innate immune response and activate antitumor adaptive responses, our finding indicates that targeted delivery and activation of STING(S162A/G230I/Q266I) in tumor cells holds great therapeutic promise for the treatment of MCC and many other STING-deficient cancers.
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