Potentiation of cancer immunity-inducing effect by pH-sensitive polysaccharide-modified liposomes with combination of TGF-β type I receptor inhibitor-embedded liposomes

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Eiji Yuba Shinya Uesugi Yuta Yoshizaki Atsushi Harada Kenji Kono


Recent success of immune checkpoint inhibitors has revealed that canceling of immunosuppression in tumor microenvironments is crucially important to achieve effective cancer immunotherapy via tumor-specific cytotoxic T lymphocytes (CTLs). Transforming growth factor (TGF)-beta signaling also contributes to immunosuppression in tumors via inactivation of CTL and activation of regulatory T cells. The combination of CTL induction system and blocking system of TGF-beta signaling is attempted in this study using antigen-loaded pH-sensitive polysaccharide-modified liposome and liposome embedded SB505124: an inhibitor of TGF-beta type I receptor. 3-Methylglutarylated dextran (MGlu-Dex)-modified liposomes delivered model antigenic protein, ovalbumin (OVA) into cytosol of dendritic cell line via pH-responsive membrane disruption and subcutaneous administration of these liposomes induced the regression of OVA-expressing tumor in mice. Additional administration of SB505124-embedded liposomes improved antitumor effects and survival in mice. Especially, intravenous administration of SB505124-embedded liposomes promoted the infiltration of CTL to tumor tissues significantly compared with single administration of MGlu-Dex-modified liposomes, leading to strong immunotherapeutic effects. Therefore, the combination of pH-sensitive polysaccharide-modified liposomes and SB-embedded liposomes is promising as an immunity-inducing system for cancer immunotherapy.

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YUBA, Eiji et al. Potentiation of cancer immunity-inducing effect by pH-sensitive polysaccharide-modified liposomes with combination of TGF-β type I receptor inhibitor-embedded liposomes. Medical Research Archives, [S.l.], v. 5, n. 5, may 2017. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/1243>. Date accessed: 25 mar. 2023.
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1. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–723.
2. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32(10):1020–1030.
3. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–571.
4. Flavell RA, Sanjabi S, Wrzesinski SH, and Licona-Limon P. The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol. 2010;10(8):554–567.
5. Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med. 2001;7(10):1118–1122.
6. Liu VC, Wong LY, Jang T, et al. Tumor evasion of the immune system by converting CD4+CD25- T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-beta. J Immunol. 2007;178(5):2883–2892.
7. Connolly EC, Freimuth J, Akhurst RJ. Complexities of TGF-β targeted cancer therapy. Int J Biol Sci. 2012;8(7):964–978.
8. Meng H, Zhao Y, Dong J, et al. Two-wave nanotherapy to target the stroma and optimize gemcitabine delivery to a human pancreatic cancer model in mice. ACS Nano. 2013;7(11):10048–10065.
9. Park J, Wrzesinski SH, Stern E, Look M, Criscione J, et al. Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy. Nat Mater. 2012;11(10):895–905.
10. Xu Z, Wang Y, Zhang L, Huang L. Nanoparticle delivered transforming growth factor-β siRNA enhances vaccination against advanced melanoma by modifying tumor microenvironment. ACS Nano. 2014;8(4):3636–3645.
11. Yuba E. Design of pH-sensitive polymer-modified liposomes for antigen delivery and their application in cancer immunotherapy. Polym J. 2016;48:761–771.
12. Yuba E, Harada A, Sakanishi Y, et al. A liposome-based antigen delivery system using pH-sensitive fusogenic polymers for cancer immunotherapy. Biomaterials. 2013;34(12):3042–3052.
13. Yuba E, Kono Y, Harada A, et al. The application of pH-sensitive polymer-lipids to antigen delivery for cancer immunotherapy. Biomaterials. 2013;34(22):5711–5721.
14. Yuba E, Tajima N, Yoshizaki Y, et al. Dextran derivative-based pH-sensitive liposomes for cancer immunotherapy. Biomaterials. 2014;35(9):3091–3101.
15. Yuba E, Yamaguchi A, Yoshizaki Y, et al. Bioactive polysaccharide-based pH-sensitive polymers for cytoplasmic delivery of antigen and activation of antigen-specific immunity. Biomaterials. 2017;120:32–45.
16. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–252.
17. Mellman I, Steinman RM. Dendritic cells: specialized and regulated antigen processing machines. Cell. 2001;106(3):255–258.
18. DaCosta-Byfield S, Major C, Laping NJ, Roberts AB. SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7. Mol Pharmacol. 2004;65(3):744–752.
19. Moore MW, Carbone FR, Bevan MJ. Introduction of soluble protein into the class I pathway of antigen processing and presentation. Cell. 1988;54(6):777–785.
20. Shen Z, Reznikoff G, Dranoff G, Rock KL. Cloned dendritic cells can present exogenous antigens on both MHC class I and class II molecules. J Immunol. 1997;158(6):2723–2730.
21. Mukherjee S, Ghosh RN, Maxfield FR. Endocytosis. Physiol Rev. 1997;77(3):759–803.
22. Barenholz Y. Doxil® – the first FDA-approved nano-drug: lessons learned. J Control Release. 2012;160(2):117–134.
23. Guo CL, Yang XH, Cheng W, et al. Expression of Fas/FasL in CD8+ T and CD3+ Foxp3+ Treg cells--relationship with apoptosis of circulating CD8+ T cells in hepatocellular carcinoma patients. Asian Pac J Cancer Prev. 2014;15(6):2613–2618.
24. Maeda H, Wu J, Sawa T, et al. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release. 2000;65(1–2):271–284.
25. Wong AD, Ye M, Ulmschneider MB, Searson PC. Quantitative analysis of the enhanced permeation and retention (EPR) effect. PLoS One. 2015;10(5):e0123461.
26. Allen TM, Hansen C, Martin F, et al. Liposomes containing synthetic lipid derivatives of poly(ethylene glycol) show prolonged circulation half-lives in vivo. Biochim Biophys Acta. 1991;1066(1):29–36.