TY - JOUR
T1 - A STING-activating nanovaccine for cancer immunotherapy
AU - Luo, Min
AU - Wang, Hua
AU - Wang, Zhaohui
AU - Cai, Haocheng
AU - Lu, Zhigang
AU - Li, Yang
AU - Du, Mingjian
AU - Huang, Gang
AU - Wang, Chensu
AU - Chen, Xiang
AU - Porembka, Matthew R.
AU - Lea, Jayanthi
AU - Frankel, Arthur E.
AU - Fu, Yang Xin
AU - Chen, Zhijian J.
AU - Gao, Jinming
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2017/7/1
Y1 - 2017/7/1
N2 - The generation of tumour-specific T cells is critically important for cancer immunotherapy. 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.
AB - The generation of tumour-specific T cells is critically important for cancer immunotherapy. 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.
UR - http://www.scopus.com/inward/record.url?scp=85018382461&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018382461&partnerID=8YFLogxK
U2 - 10.1038/nnano.2017.52
DO - 10.1038/nnano.2017.52
M3 - Article
C2 - 28436963
AN - SCOPUS:85018382461
VL - 12
SP - 648
EP - 654
JO - Nature Nanotechnology
JF - Nature Nanotechnology
SN - 1748-3387
IS - 7
ER -