Peptide-Based Cancer Vaccine Delivery via the STINGΔTM-cGAMP Complex
Yanpu He1,2, Celestine Hong1,2, Samantha J Fletcher1,2
1Koch Institute for Integrative Cancer Research, Cambridge, MA, 02139, USA.
Abstract:
With the advent of bioinformatic tools in efficiently predicting neo-antigens, peptide vaccines have gained tremendous attention in cancer immunotherapy. However, the delivery of peptide vaccines remains a major challenge, primarily due to ineffective transport to lymph nodes and low immunogenicity. Here, a strategy for peptide vaccine delivery is reported by first fusing the peptide to the cytosolic domain of the stimulator of interferon genes protein (STINGΔTM), then complexing the peptide-STINGΔTM protein with STING agonist 2'3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). The process results in the formation of self-assembled cGAMP-peptide-STINGΔTM tetramers, which enables efficient lymphatic trafficking of the peptide. Moreover, the cGAMP-STINGΔTM complex acts not only as a protein carrier for the peptide, but also as a potent adjuvant capable of triggering STING signaling independent of endogenous STING protein-an especially important attribute considering that certain cancer cells epigenetically silence their endogenous STING expression. With model antigen SIINFEKL, it is demonstrated that the platform elicits effective STING signaling in vitro, draining lymph node targeting in vivo, effective T cell priming in vivo as well as antitumoral immune response in a mouse colon carcinoma model, providing a versatile solution to the challenges faced in peptide vaccine delivery.
Insights
This study introduces a novel peptide vaccine delivery system using STING agonist cGAMP and STINGΔTM protein. This self-assembled tetramer enhances lymphatic transport and immunogenicity for effective cancer immunotherapy.
Area of Science:
- Immunology
- Biotechnology
- Oncology
Background:
- Peptide vaccines are promising for cancer immunotherapy but face delivery and immunogenicity challenges.
- Ineffective transport to lymph nodes and low immunogenicity hinder peptide vaccine efficacy.
- Cancer cells can downregulate endogenous stimulator of interferon genes (STING) protein, impacting immunotherapy response.
Purpose of the Study:
- To develop an improved peptide vaccine delivery system that overcomes current limitations.
- To enhance lymphatic trafficking and immunogenicity of peptide vaccines.
- To create a delivery platform that bypasses the need for endogenous STING signaling.
Main Methods:
- Fusing peptides to the cytosolic domain of STING (STINGΔTM).
- Complexing peptide-STINGΔTM with STING agonist 2'3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP).
- Forming self-assembled cGAMP-peptide-STINGΔTM tetramers for vaccine delivery.
Main Results:
- The cGAMP-peptide-STINGΔTM tetramers demonstrated efficient lymphatic trafficking in vivo.
- The platform effectively triggered STING signaling independently of endogenous STING.
- Demonstrated effective T cell priming and antitumoral immune response in a mouse colon carcinoma model.
Conclusions:
- The developed platform offers a versatile solution for peptide vaccine delivery challenges in cancer immunotherapy.
- Self-assembled cGAMP-peptide-STINGΔTM tetramers enhance vaccine transport and adjuvant properties.
- This approach holds potential for overcoming STING silencing in cancer cells and improving therapeutic outcomes.
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