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In vitro and in vivo evaluation of DC-targeting PLGA nanoparticles encapsulating heparanase CD4+ and CD8+ T-cell epitopes for cancer immunotherapy

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Abstract

Heparanase has been identified as a universal tumor-associated antigen, but heparanase epitope peptides are difficult to recognize. Therefore, it is necessary to explore novel strategies to ensure efficient delivery to antigen-presenting cells. Here, we established a novel immunotherapy model targeting antigens to dendritic cell (DC) receptors using a combination of heparanase CD4+ and CD8+ T-cell epitope peptides to achieve an efficient cytotoxic T-cell response, which was associated with strong activation of DCs. First, pegylated poly(lactic-coglycolic acid) (PLGA) nanoparticles (NPs) were used to encapsulate a combined heparanase CD4+ and CD8+ T-cell epitope alone or in combination with Toll-like receptor 3 and 7 ligands as a model antigen to enhance immunogenicity. The ligands were then targeted to DC cell-surface molecules using a DEC-205 antibody. The binding and internalization of these PLGA NPs and the activation of DCs, the T-cell response and the tumor-killing effect were assessed. The results showed that PLGA NPs encapsulating epitope peptides (mHpa399 + mHpa519) could be targeted to and internalized by DCs more efficiently, stimulating higher levels of IL-12 production, T-cell proliferation and IFN-γ production by T cells in vitro. Moreover, vaccination with DEC-205-targeted PLGA NPs encapsulating combined epitope peptides exhibited higher tumor-killing efficacy both in vitro and in vivo. In conclusion, delivery of PLGA NP vaccines targeting DEC-205 based on heparanase CD4+ and CD8+ T-cell epitopes are suitable immunogens for antitumor immunotherapy and have promising potential for clinical applications.

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References

  1. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331(6024):1565–1570

    Article  CAS  PubMed  Google Scholar 

  2. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ (2011) Natural innate and adaptive immunity to cancer. Annu Rev Immunol 29:235–271

    Article  CAS  PubMed  Google Scholar 

  3. Finn OJ (2014) Vaccines for cancer prevention: a practical and feasible approach to the cancer epidemic. Cancer Immunol Res 2(8):708–713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T (2014) Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer 14(2):135–146

    Article  CAS  PubMed  Google Scholar 

  5. Hinrichs CS, Restifo NP (2013) Reassessing target antigens for adoptive T-cell therapy. Reassessing target antigens for adoptive T-cell therapy. Nat Biotechnol 31(11):999–1008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Novellino L, Castelli C, Parmiani G (2005) A listing of human tumor antigens recognized by T cells: March 2004 update. Cancer Immunol Immunother 54(3):187–207

    Article  CAS  PubMed  Google Scholar 

  7. Nishimura Y, Tomita Y, Yuno A, Yoshitake Y, Shinohara M (2015) Cancer immunotherapy using novel tumor-associated antigenic peptides identified by genome-wide cDNA microarray analyses. Cancer Sci 106(5):505–511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hammond E, Khurana A, Shridhar V, Dredge K (2014) The role of heparanase and sulfatases in the modification of heparan sulfate proteoglycans within the tumor microenvironment and opportunities for novel cancer therapeutics. Front Oncol 4:195

    Article  PubMed  PubMed Central  Google Scholar 

  9. Barash U, Cohen-Kaplan V, Dowek I, Sanderson RD, Ilan N, Vlodavsky I (2010) Proteoglycans in health and disease: new concepts for heparanase function in tumor progression and metastasis. FEBS J 277(19):3890–3903

    Article  CAS  PubMed  Google Scholar 

  10. Rivara S, Milazzo FM, Giannini G (2016) Heparanase: a rainbow pharmacological target associated to multiple pathologies including rare diseases. Future Med Chem 8(6):647–680

    Article  CAS  PubMed  Google Scholar 

  11. Masola V, Secchi MF, Gambaro G, Onisto M (2014) Heparanase as a target in cancer therapy. Curr Cancer Drug Targets 14(3):286–293

    Article  CAS  PubMed  Google Scholar 

  12. Pisano C, Vlodavsky I, Ilan N, Zunino F (2014) The potential of heparanase as a therapeutic target in cancer. Biochem Pharmacol 89(1):12–19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Vlodavsky I, Beckhove P, Lerner I, Pisano C, Meirovitz A, Ilan N, Elkin M (2012) Significance of heparanase in cancer and inflammation. Cancer Microenviron 5(2):115–132

    Article  CAS  PubMed  Google Scholar 

  14. Tang XD, Wan Y, Chen L, Chen T, Yu ST, Xiong Z, Fang DC, Liang GP, Yang SM (2008) H-2Kb-restricted CTL epitopes from mouse heparanase elicit an antitumor immune response in vivo. Cancer Res 68(5):1529–1537

    Article  CAS  PubMed  Google Scholar 

  15. Tang XD, Wang GZ, Guo J, Lü MH, Li C, Li N, Chao YL, Li CZ, Wu YY, Hu CJ, Fang DC, Yang SM (2012) Multiple antigenic peptides based on H-2K(b)-restricted CTL epitopes from murine heparanase induce a potent antitumor immune response in vivo. Mol Cancer Ther 11(5):1183–1192

    Article  CAS  PubMed  Google Scholar 

  16. Rammensee HG, Falk K, Rötzschke O (1993) Peptides naturally presented by MHC class I molecules. Annu Rev Immunol 11:213–244

    Article  CAS  PubMed  Google Scholar 

  17. Chen T, Tang XD, Wan Y, Chen L, Yu ST, Xiong Z, Fang DC, Liang GP, Yang SM (2008) HLA-A2-restricted cytotoxic T lymphocyte epitopes from human heparanase as novel targets for broad-spectrum tumor immunotherapy. Neoplasia 10(9):977–986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tang XD, Liang GP, Li C, Wan Y, Chen T, Chen L, Yu ST, Xiong Z, Fang DC, Wang GZ, Yang SM (2010) Cytotoxic T lymphocyte epitopes from human heparanase can elicit a potent anti-tumor immune response in mice. Cancer Immunol Immunother 59(7):1041–1047

    Article  CAS  PubMed  Google Scholar 

  19. Wang HY, Wang RF (2012) Enhancing cancer immunotherapy by intracellular delivery of cell-penetrating peptides and stimulation of pattern-recognition receptor signaling. Adv Immunol 114:151–176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang RF, Wang HY (2017) Immune targets and neoantigens for cancer immunotherapy and precision medicine. Cell Res 27(1):11–37

    Article  PubMed  Google Scholar 

  21. Borst J, Ahrends T, Bąbała N, Melief CJM, Kastenmüller W (2018) CD4+ T cell help in cancer immunology and immunotherapy. Nat Rev Immunol 18(10):635–647

    Article  CAS  PubMed  Google Scholar 

  22. Lövgren T, Sarhan D, Truxová I et al (2017) Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists. Cancer Immunol Immunother 66(10):1333–1344

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zhou CX, Li D, Chen YL et al (2014) Resiquimod and polyinosinic-polycytidylic acid formulation with aluminum hydroxide as an adjuvant for foot-and-mouth disease vaccine. BMC Vet Res 10:2

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kapadia CH, Perry JL, Tian S, Luft JC, DeSimone JM (2015) Nanoparticulate immunotherapy for cancer. J Control Release 219:167–180

    Article  CAS  PubMed  Google Scholar 

  25. Cho K, Wang X, Nie S, Chen ZG, Shin DM (2008) Therapeutic nanoparticles for drug delivery in cancer. Clin Cancer Res 14(5):1310–1316

    Article  CAS  PubMed  Google Scholar 

  26. Zamboni WC, Torchilin V, Patri AK, Hrkach J, Stern S, Lee R, Nel A, Panaro NJ, Grodzinski P (2012) Best practices in cancer nanotechnology: perspective from NCI nanotechnology alliance. Clin Cancer Res 18(12):3229–3241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zang X, Zhao X, Hu H, Qiao M, Deng Y, Chen D (2017) Nanoparticles for tumor immunotherapy. Eur J Pharm Biopharm 115:243–256

    Article  CAS  PubMed  Google Scholar 

  28. Decker WK, Xing D, Shpall EJ (2006) Dendritic cell immunotherapy for the treatment of neoplastic disease. Biol Blood Marrow Transplant 12(2):113–125

    Article  PubMed  Google Scholar 

  29. Bevan MJ (2004) Helping the CD8(+) T-cell response. Nat Rev Immunol 4(8):595–602

    Article  CAS  PubMed  Google Scholar 

  30. Bos R, Sherman LA (2010) CD4+ T-cell help in the tumor milieu is required for recruitment and cytolytic function of CD8+ T lymphocytes. Cancer Res 70(21):8368–8377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nakanishi Y, Lu B, Gerard C, Iwasaki A (2009) CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature 462(7272):510–513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhu Z, Cuss SM, Singh V et al (2015) CD4+ T cell help selectively enhances high-avidity tumor antigen-specific CD8+ T cells. J Immunol 195(7):3482–3489

    Article  CAS  PubMed  Google Scholar 

  33. Wick DA, Martin SD, Nelson BH, Webb JR (2011) Profound CD8+ T cell immunity elicited by sequential daily immunization with exogenous antigen plus the TLR3 agonist poly(I:C). Vaccine 29(5):984–993

    Article  CAS  PubMed  Google Scholar 

  34. Cruz LJ, Rosalia RA, Kleinovink JW, Rueda F, Löwik CW, Ossendorp F (2014) Targeting nanoparticles to CD40, DEC-205 or CD11c molecules on dendritic cells for efficient CD8(+) T cell response: a comparative study. J Control Release 192:209–218

    Article  CAS  PubMed  Google Scholar 

  35. Geijtenbeek TB, Gringhuis SI (2009) Signalling through C-type lectin receptors: shaping immune responses. Nat Rev Immunol 9(7):465–479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Elgueta R, Benson MJ, de Vries VC, Wasiuk A, Guo Y, Noelle RJ (2009) Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev 229(1):152–172

    Article  CAS  PubMed  Google Scholar 

  37. Zhang Z, Tongchusak S, Mizukami Y, Kang YJ, Ioji T, Touma M, Reinhold B, Keskin DB, Reinherz EL, Sasada T (2011) Induction of anti-tumor cytotoxic T cell responses through PLGA-nanoparticle mediated antigen delivery. Biomaterials 32(14):3666–3678

    Article  CAS  PubMed  Google Scholar 

  38. Manolova V, Flace A, Bauer M, Schwarz K, Saudan P, Bachmann MF (2008) Nanoparticles target distinct dendritic cell populations according to their size. Eur J Immunol 38(5):1404–1413

    Article  CAS  PubMed  Google Scholar 

  39. Raghuwanshi D, Mishra V, Suresh MR, Kaur K (2012) A simple approach for enhanced immune response using engineered dendritic cell targeted nanoparticles. Vaccine 30(50):7292–7299

    Article  CAS  PubMed  Google Scholar 

  40. Tacken PJ, Figdor CG (2011) Targeted antigen delivery and activation of dendritic cells in vivo: steps towards cost effective vaccines. Semin Immunol 23(1):12–20

    Article  CAS  PubMed  Google Scholar 

  41. Burgdorf S, Kurts C (2008) Endocytosis mechanisms and the cell biology of antigen presentation. Curr Opin Immunol 20(1):89–95

    Article  CAS  PubMed  Google Scholar 

  42. Tsoi KM, MacParland SA, Ma XZ, Spetzler VN, Echeverri J, Ouyang B, Fadel SM, Sykes EA, Goldaracena N, Kaths JM, Conneely JB, Alman BA, Selzner M, Ostrowski MA, Adeyi OA, Zilman A, McGilvray ID, Chan WC (2016) Mechanism of hard-nanomaterial clearance by the liver. Nat Mater 15(11):1212–1221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Danhier F, Ansorena E, Silva JM, Coco R, Le Breton A, Préat V (2012) PLGA-based nanoparticles: an overview of biomedical applications. J Control Release 161(2):505–522

    Article  CAS  PubMed  Google Scholar 

  44. Min Y, Roche KC, Tian S, Eblan MJ, McKinnon KP, Caster JM, Chai S, Herring LE, Zhang L, Zhang T, DeSimone JM, Tepper JE, Vincent BG, Serody JS, Wang AZ (2017) Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy. Nat Nanotechnol 12(9):877–882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liu L, Cao F, Liu X, Wang H, Zhang C, Sun H, Wang C, Leng X, Song C, Kong D, Ma G (2016) Hyaluronic acid-modified cationic lipid-PLGA hybrid nanoparticles as a nanovaccine induce robust humoral and cellular immune responses. ACS Appl Mater Interfaces 8(19):11969–11979

    Article  CAS  PubMed  Google Scholar 

  46. Jahan ST, Sadat SMA, Yarahmadi M, Haddadi A (2019) Potentiating antigen specific immune response by targeted delivery of the PLGA-based model cancer vaccine. Mol Pharm 16(2):498–509

    Article  CAS  PubMed  Google Scholar 

  47. Hänel G, Angerer C, Petry K, Lichtenegger FS, Subklewe M (2021) Blood DCs activated with R848 and poly(I:C) induce antigen-specific immune responses against viral and tumor-associated antigens. Cancer Immunol Immunother CII:1–14

    Google Scholar 

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Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (No. 81372470), and the Chongqing Science and Technology Commission Frontier and Applied Basic Research General Project (Project Number Nos. CSTCjcyjmsxmX0634, CSTC2014jcyjA10100, and cstc2019jcyj-msxmX0791).

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Author notes

  1. Xu-Dong Tang, Kui-Lin Lü and Jin Yu contributed equally to this study.

Authors and Affiliations

  1. Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China

    Xu-Dong Tang & Lei Chen

  2. Department of Pediatrics, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China

    Kui-Lin Lü

  3. Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China

    Jin Yu & Chao-Qiang Fan

  4. Department of Neurosurgery, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing, 400030, China

    Han-Jian Du

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  1. Xu-Dong Tang
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Correspondence to Chao-Qiang Fan or Lei Chen.

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Tang, XD., Lü, KL., Yu, J. et al. In vitro and in vivo evaluation of DC-targeting PLGA nanoparticles encapsulating heparanase CD4+ and CD8+ T-cell epitopes for cancer immunotherapy. Cancer Immunol Immunother 71, 2969–2983 (2022). https://doi.org/10.1007/s00262-022-03209-1

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