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Published on: June 10, 2022
Lipid Nanoparticles Delivering Constitutively Active STING mRNA to Stimulate Antitumor Immunity
Wei Liu1, Mohamad-Gabriel Alameh2, June F Yang1
1Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Abstract:
Treating immunosuppressive tumors represents a major challenge in cancer therapies. Activation of STING signaling has shown remarkable potential to invigorate the immunologically "cold" tumor microenvironment (TME). However, we have shown that STING is silenced in many human cancers, including pancreatic ductal adenocarcinoma (PDAC) and Merkel cell carcinoma (MCC). In this study, we demonstrated that mRNA-lipid nanoparticle (LNP) technology could be used to efficiently deliver naturally occurring constitutively active STING mutant STINGR284S into these cancer cells to reactivate STING antitumor immunity and trigger robust killing of tumor cells. STING agonists are being actively pursued as cancer immunotherapies. However, traditional STING agonists can induce T cell cytotoxicity, counteracting the desired antitumor immune response. In addition, the antitumor efficacy of traditional STING agonists obligatorily depends on STING expression and does not work in STING-silenced cancers. Importantly, we found that STINGR284S mRNA-LNP does not introduce T cell cytotoxicity. Our studies demonstrated that mRNA-LNP delivery of STINGR284S can reactivate the antitumor response without introducing antiproliferative effects in lymphocytic immune cells, overcoming the toxicity and limitations of conventional STING agonists. Our work therefore identifies a novel therapeutic tool for reactivating antitumor immunity in an array of STING-silenced immunologically "cold" tumors that are refractory to current therapies.
Insights
Messenger RNA (mRNA) lipid nanoparticle (LNP) technology delivers a STING mutant (STINGR284S) to reactivate antitumor immunity in STING-silenced cancers. This approach avoids T cell cytotoxicity, offering a novel therapy for cold tumors.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Immunosuppressive tumors pose a significant challenge in cancer therapy.
- STING (stimulator of interferon genes) signaling activation can enhance the tumor microenvironment (TME).
- STING is frequently silenced in human cancers like pancreatic ductal adenocarcinoma (PDAC) and Merkel cell carcinoma (MCC).
Purpose of the Study:
- To investigate the potential of mRNA-lipid nanoparticle (LNP) technology for delivering a constitutively active STING mutant (STINGR284S) into cancer cells.
- To evaluate the ability of STINGR284S mRNA-LNP to reactivate antitumor immunity in STING-silenced tumors.
- To assess whether STINGR284S mRNA-LNP delivery avoids the T cell cytotoxicity associated with traditional STING agonists.
Main Methods:
- Utilized mRNA-lipid nanoparticle (LNP) technology for gene delivery.
- Delivered a naturally occurring, constitutively active STING mutant (STINGR284S) into cancer cells.
- Assessed the reactivation of STING antitumor immunity and tumor cell killing.
- Evaluated T cell cytotoxicity and antiproliferative effects on immune cells.
Main Results:
- mRNA-LNP technology efficiently delivered STINGR284S into cancer cells, reactivating STING antitumor immunity.
- STINGR284S delivery triggered robust tumor cell killing in STING-silenced cancers.
- STINGR284S mRNA-LNP did not induce T cell cytotoxicity, unlike traditional STING agonists.
- The treatment reactivated antitumor responses without antiproliferative effects on lymphocytic immune cells.
Conclusions:
- mRNA-LNP delivery of STINGR284S is a viable strategy to overcome STING silencing in tumors.
- This approach effectively reactivates antitumor immunity and promotes tumor cell killing.
- STINGR284S mRNA-LNP offers a safer alternative to conventional STING agonists by avoiding T cell toxicity.
- This novel therapeutic tool holds promise for treating STING-silenced, immunotherapy-refractory cold tumors.
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