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Tumour sensitization via the extended intratumoural release of a STING agonist and camptothecin from a self-assembled hydrogel

Abstract

Tumours with an immunosuppressive microenvironment respond poorly to therapy. Activation of the stimulator of interferon genes (STING) pathway can enhance intratumoural immune activation, but STING agonists are associated with high toxicity and degrade prematurely, which limits their effectiveness. Here, we show that the extended intratumoural release of the STING agonist cyclic di-AMP transforms the tumour microenvironment from immunosuppressive to immunostimulatory, increasing the efficacy of antitumour therapies. The STING agonist was electrostatically complexed with nanotubes comprising a peptide–drug conjugate (a peptide that binds to the protein neuropilin-1, which is highly expressed in tumours, and the chemotherapeutic agent camptothecin) that self-assemble in situ into a supramolecular hydrogel. In multiple mouse models of murine tumours, a single low dose of the STING agonist led to tumour regression and increased animal survival, and to long-term immunological memory and systemic immune surveillance, which protected the mice against tumour recurrence and the formation of metastases. Locally delivered STING agonists could help to reduce tumour immunosuppression and enhance the efficacy of a wide range of cancer therapies.

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Fig. 1: Schematic and characterization of the in situ-formed chemoimmunotherapeutic supramolecular hydrogel.
Fig. 2: Biodegradable diCPT–iRGD nanotube hydrogel enables local retention and extended release of CDA.
Fig. 3: Local delivery of CDA by CPT-based NT hydrogels elicits regression of established GL-261 brain tumours.
Fig. 4: The important role of the STING pathway in stimulating innate and adaptive immune responses for effective tumour regression by CDA–NT.
Fig. 5: CDA–NT induces T-cell memory and a durable antitumour immune response.
Fig. 6: Local treatment with CDA–NT hydrogels promoted regression of low-immunogenic 4T1 breast cancers.

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Data availability

All data supporting the findings of this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, yet they are available for research purposes from the corresponding author on reasonable request.

References

  1. Royal, R. E. et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 33, 828–833 (2010).

    CAS  Google Scholar 

  2. Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).

    CAS  Google Scholar 

  3. Tang, H. et al. Facilitating T cell infiltration in tumor microenvironment overcomes resistance to PD-L1 blockade. Cancer Cell 29, 285–296 (2016).

    CAS  Google Scholar 

  4. Zou, W., Wolchok, J. D. & Chen, L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci. Transl. Med. 8, 328rv324 (2016).

    Google Scholar 

  5. Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017).

    CAS  Google Scholar 

  6. Gajewski, T. F., Schreiber, H. & Fu, Y. X. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14, 1014–1022 (2013).

    CAS  Google Scholar 

  7. Joyce, J. A. & Fearon, D. T. T cell exclusion, immune privilege, and the tumor microenvironment. Science 348, 74–80 (2015).

    CAS  Google Scholar 

  8. Binnewies, M. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018).

    CAS  Google Scholar 

  9. Cook, A. M., Lesterhuis, W. J., Nowak, A. K. & Lake, R. A. Chemotherapy and immunotherapy: mapping the road ahead. Curr. Opin. Immunol. 39, 23–29 (2016).

    CAS  Google Scholar 

  10. Galon, J. & Bruni, D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat. Rev. Drug Discov. 18, 197–218 (2019).

    CAS  Google Scholar 

  11. Barber, G. N. STING: infection, inflammation and cancer. Nat. Rev. Immunol. 15, 760–770 (2015).

    CAS  Google Scholar 

  12. Rivera Vargas, T., Benoit-Lizon, I. & Apetoh, L. Rationale for stimulator of interferon genes-targeted cancer immunotherapy. Eur. J. Cancer 75, 86–97 (2017).

    CAS  Google Scholar 

  13. Ishikawa, H. & Barber, G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).

    CAS  Google Scholar 

  14. Wu, J. et al. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339, 826–830 (2013).

    CAS  Google Scholar 

  15. Ablasser, A. et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature 498, 380–384 (2013).

    CAS  Google Scholar 

  16. Ishikawa, H., Ma, Z. & Barber, G. N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009).

    CAS  Google Scholar 

  17. Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z. J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791 (2013).

    CAS  Google Scholar 

  18. Diamond, M. S. et al. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J. Exp. Med. 208, 1989–2003 (2011).

    CAS  Google Scholar 

  19. Fuertes, M. B. et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cells. J. Exp. Med. 208, 2005–2016 (2011).

    CAS  Google Scholar 

  20. Takashima, K. et al. STING in tumor and host cells cooperatively work for NK cell-mediated tumor growth retardation. Biochem. Biophys. Res. Commun. 478, 1764–1771 (2016).

    CAS  Google Scholar 

  21. Marcus, A. et al. Tumor-derived cGAMP Triggers a STING-Mediated interferon response in non-tumor cells to activate the NK cell response. Immunity 49, 754–763 (2018).

    CAS  Google Scholar 

  22. Corrales, L. et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 11, 1018–1030 (2015).

    CAS  Google Scholar 

  23. Demaria, O. et al. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc. Natl Acad. Sci. USA 112, 15408–15413 (2015).

    CAS  Google Scholar 

  24. Fu, J. et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci. Transl. Med. 7, 283ra252 (2015).

    Google Scholar 

  25. Moore, E. et al. Established T cell-inflamed tumors rejected after adaptive resistance was reversed by combination STING activation and PD-1 pathway blockade. Cancer Immunol. Res. 4, 1061–1071 (2016).

    CAS  Google Scholar 

  26. Koshy, S. T., Cheung, A. S., Gu, L., Graveline, A. R. & Mooney, D. J. Liposomal delivery enhances immune activation by STING agonists for cancer immunotherapy. Adv. Biosyst. 1, 1600013 (2017).

    Google Scholar 

  27. Park, C. G. et al. Extended release of perioperative immunotherapy prevents tumor recurrence and eliminates metastases. Sci. Transl. Med. 10, eaar1916 (2018).

    Google Scholar 

  28. Shae, D. et al. Endosomolytic polymersomes increase the activity of cyclic dinucleotide STING agonists to enhance cancer immunotherapy. Nat. Nanotechnol. 14, 269–278 (2019).

    CAS  Google Scholar 

  29. Burden, D. A. & Osheroff, N. Mechanism of action of eukaryotic topoisomerase II and drugs targeted to the enzyme. Biochim. Biophys. Acta 1400, 139–154 (1998).

    CAS  Google Scholar 

  30. Liu, L. F. et al. Mechanism of action of camptothecin. Ann. N. Y. Acad. Sci. 922, 1–10 (2000).

    CAS  Google Scholar 

  31. Ahn, J., Ruiz, P. & Barber, G. N. Intrinsic self-DNA triggers inflammatory disease dependent on STING. J. Immunol. 193, 4634–4642 (2014).

    CAS  Google Scholar 

  32. Zitvogel, L., Galluzzi, L., Smyth, M. J. & Kroemer, G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 39, 74–88 (2013).

    CAS  Google Scholar 

  33. Lombardi, G. et al. Clinical and genetic factors associated with severe hematological toxicity in glioblastoma patients during radiation plus temozolomide treatment: a prospective study. Am. J. Clin. Oncol. 38, 514–519 (2015).

    CAS  Google Scholar 

  34. Mathios, D. et al. Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM. Sci. Transl. Med. 8, 370ra180 (2016).

    Google Scholar 

  35. Wang, C. et al. In situ formed reactive oxygen species-responsive scaffold with gemcitabine and checkpoint inhibitor for combination therapy. Sci. Transl. Med. 10, eaan3682 (2018).

    Google Scholar 

  36. Sugahara, K. N. et al. Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 16, 510–520 (2009).

    CAS  Google Scholar 

  37. Cheetham, A. G., Ou, Y. C., Zhang, P. & Cui, H. Linker-determined drug release mechanism of free camptothecin from self-assembling drug amphiphiles. Chem. Commun. 50, 6039–6042 (2014).

    CAS  Google Scholar 

  38. Spitzer, M. H. et al. Systemic immunity is required for effective cancer immunotherapy. Cell 168, 487–502 (2017).

    CAS  Google Scholar 

  39. Spel, L., Boelens, J. J., Nierkens, S. & Boes, M. Antitumor immune responses mediated by dendritic cells: how signals derived from dying cancer cells drive antigen cross-presentation. Oncoimmunology 2, e26403 (2013).

    Google Scholar 

  40. Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).

    CAS  Google Scholar 

  41. Chandra, D. et al. STING ligand c-di-GMP improves cancer vaccination against metastatic breast cancer. Cancer Immunol. Res. 2, 901–910 (2014).

    CAS  Google Scholar 

  42. Devaud, C. et al. Tissues in different anatomical sites can sculpt and vary the tumor microenvironment to affect responses to therapy. Mol. Ther. 22, 18–27 (2014).

    CAS  Google Scholar 

  43. Deng, W. et al. Recombinant Listeria promotes tumor rejection by CD8+ T cell-dependent remodeling of the tumor microenvironment. Proc. Natl Acad. Sci. USA 115, 8179–8184 (2018).

    CAS  Google Scholar 

  44. Scrimieri, F. et al. Murine leukemia virus envelope gp70 is a shared biomarker for the high-sensitivity quantification of murine tumor burden. Oncoimmunology 2, e26889 (2013).

    Google Scholar 

  45. van der Most, R. G., Robinson, B. W. & Lake, R. A. Combining immunotherapy with chemotherapy to treat cancer. Discov. Med. 5, 265–270 (2005).

    Google Scholar 

  46. Gadkaree, S. K. et al. Induction of tumor regression by intratumoral STING agonists combined with anti-programmed death-L1 blocking antibody in a preclinical squamous cell carcinoma model. Head Neck 39, 1086–1094 (2017).

    Google Scholar 

  47. Leach, D. G. et al. STINGel: controlled release of a cyclic dinucleotide for enhanced cancer immunotherapy. Biomaterials 163, 67–75 (2018).

    CAS  Google Scholar 

  48. Wilson, D. R. et al. Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy. Nanomedicine 14, 237–246 (2018).

    CAS  Google Scholar 

  49. Chen, Q. et al. In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment. Nat. Nanotechnol. 14, 89–97 (2019).

    CAS  Google Scholar 

  50. Peppas, N. A. & Khademhosseini, A. Make better, safer biomaterials. Nature 540, 335–336 (2016).

    CAS  Google Scholar 

  51. Wang, F. et al. Supramolecular prodrug hydrogelator as an immune booster for checkpoint blocker-based immunotherapy. Sci. Adv. 6, eaaz8985 (2020).

    Google Scholar 

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Acknowledgements

We thank M. Lim, J. Hanes and J. Fu from Johns Hopkins University School of Medicine for sharing the GL-261-luc, 4T1-luc and CT26 cells, respectively; and Q. Huang and Y. Guan for their support relating to cryosectioning. The research is supported by Johns Hopkins University Discovery Award. The flow cytometry study was partially supported by NIH grant nos. GM111682 and AI137719 (to F.Wan), and D.X. was supported by a Career in Immunology Fellowship from AAI.

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F.Wang and H.C. participated in the conception and design of the study. F.Wang and H.S. performed the majority of experiments and data analysis. F.Wang and D.X. performed the flow cytometry study and F.Wan helped to interpret the results. W.D., W.Z., Z.W., M.Z. and R.O. assisted with animal studies. F.Wang and H.S. analysed and interpreted the data. F.Wang, C.F.A. and H.C. designed and wrote the manuscript.

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Correspondence to Honggang Cui.

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Wang, F., Su, H., Xu, D. et al. Tumour sensitization via the extended intratumoural release of a STING agonist and camptothecin from a self-assembled hydrogel. Nat Biomed Eng 4, 1090–1101 (2020). https://doi.org/10.1038/s41551-020-0597-7

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