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A STING-activating nanovaccine for cancer immunotherapy

Abstract

The generation of tumour-specific T cells is critically important for cancer immunotherapy1,2. A major challenge in achieving a robust T-cell response is the spatiotemporal orchestration of antigen cross-presentation in antigen-presenting cells with innate stimulation. Here, we report a minimalist nanovaccine, comprising a simple physical mixture of an antigen and a synthetic polymeric nanoparticle, PC7A NP, which generates a strong cytotoxic T-cell response with low systemic cytokine expression. Mechanistically, the PC7A NP achieves efficient cytosolic delivery of tumour antigens to antigen-presenting cells in draining lymph nodes, leading to increased surface presentation while simultaneously activating type I interferon-stimulated genes. This effect is dependent on stimulator of interferon genes (STING), but not the Toll-like receptor or the mitochondrial antiviral-signalling protein (MAVS) pathway. The nanovaccine led to potent tumour growth inhibition in melanoma, colon cancer and human papilloma virus-E6/E7 tumour models. The combination of the PC7A nanovaccine and an anti-PD-1 antibody showed great synergy, with 100% survival over 60 days in a TC-1 tumour model. Rechallenging of these tumour-free animals with TC-1 cells led to complete inhibition of tumour growth, suggesting the generation of long-term antitumour memory. The STING-activating nanovaccine offers a simple, safe and robust strategy in boosting anti-tumour immunity for cancer immunotherapy.

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Figure 1: PC7A NPs induce robust antigen-specific CTL, Th1 and Th2 responses.
Figure 2: PC7A NPs improve antigen delivery and cross-presentation in APCs and stimulate CD8 T-cell responses.
Figure 3: PC7A NPs activate APCs in draining lymph nodes and stimulate STING-dependent adaptive immune responses.
Figure 4: PC7A nanovaccine inhibits tumour growth and prolongs survival in tumour-bearing mice.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (R01AI093967 to Z.J.C., R01EB013149 and R01CA192221 to J.G.) and the Cancer Prevention and Research Institute of Texas (RP120718-P3 and RP150498 to Z.J.C.). Z.J.C. is an Investigator of the Howard Hughes Medical Institute. M.R.P. is a Dedman Scholar in Clinical Care. Animal imaging work is supported by a UT Southwestern Small Animal Imaging Resource Grant (U24 CA126608) and a Simmons Cancer Center Support Grant (P30 CA142543). The authors thank Z. Zeng for cell culture, Q. Wei for polymer synthesis and T. Zhao for animal imaging. The authors also thank N. Yan for discussions on STING activation, T.C. Wu for providing the TC-1 tumour cells, P. Hwu for the B16-OVA cancer cells, Y. Peng for vaccine safety analysis, S. Tso for ITC experiments and the molecular pathology core of UT Southwestern for tissue toxicity analysis.

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M.L. and Z.W. designed and performed the majority of experiments, analysed the data and wrote the first draft of the paper. H.W. made the initial observation of the immune stimulatory activity of PC7A and performed the experiments on CD8 T cell activation by PC7A in vitro and in vivo. H.C. analysed innate cytokine expression in local tissues and cell lines. Z.L. assisted with the CTL and Th1 experiments. Y.L. and M.D. assisted with the PC7A and STING interaction experiments. G.H. and C.W. assisted with animal efficacy evaluation. X.C. assisted with transgenic mice studies. Y.F. assisted with PD-L1 expression in B16 and TC-1 tumours. M.R.P., J.L. and A.E.F. contributed to experimental designs. Z.J.C. and J.G. supervised all the experiments and revised the final manuscript.

Corresponding authors

Correspondence to Zhijian J. Chen or Jinming Gao.

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Luo, M., Wang, H., Wang, Z. et al. A STING-activating nanovaccine for cancer immunotherapy. Nature Nanotech 12, 648–654 (2017). https://doi.org/10.1038/nnano.2017.52

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