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Oral administration of a whole glucan particle (WGP)-based therapeutic cancer vaccine targeting macrophages inhibits tumor growth

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Abstract

Although therapeutic cancer vaccines have been gaining substantial ground, the development of cancer vaccines is impeded because of the undegradability of delivery systems, ineffective delivery of tumor antigens and weak immunogenicity of adjuvants. Here, we made use of a whole glucan particle (WGP) to encapsulate ovalbumin (OVA), thereby formulating a novel cancer vaccine. Results from in vitro experiments showed that WGP-OVA not only induced the activation of bone marrow-derived macrophages (BMDMs) including driving M0 BMDM polarization to the M1 phenotype, upregulating the costimulatory molecules and inducing the generation of cytokines, but also facilitated antigen presentation. After oral administration of the WGP-OVA formulation to mice with OVA-expressing tumors, these particles can increase tumor-infiltrating OVA-specific CD8+ CTLs and repolarize tumor-associated macrophages (TAMs) toward M1-like phenotype, which led to delayed tumor progression. These findings revealed that WGP could serve as both an antigen delivery system and an adjuvant system for promising cancer vaccines.

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References

  1. Banday AH, Jeelani S, Hruby VJ (2015) Cancer vaccine adjuvants–recent clinical progress and future perspectives. Immunopharmacol Immunotoxicol 37(1):1–11. https://doi.org/10.3109/08923973.2014.971963

    Article  CAS  PubMed  Google Scholar 

  2. Zhang R, Billingsley MM, Mitchell MJ (2018) Biomaterials for vaccine-based cancer immunotherapy. J Control Release 292:256–276. https://doi.org/10.1016/j.jconrel.2018.10.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Deng C, Hu Z, Fu H, Hu M, Xu X, Chen J (2012) Chemical analysis and antioxidant activity in vitro of a beta-D-glucan isolated from Dictyophora indusiata. Int J Biol Macromol 51(1–2):70–75. https://doi.org/10.1016/j.ijbiomac.2012.05.001

    Article  CAS  PubMed  Google Scholar 

  4. Qi C, Cai Y, Gunn L, Ding C, Li B, Kloecker G et al (2011) Differential pathways regulating innate and adaptive antitumor immune responses by particulate and soluble yeast-derived beta-glucans. Blood 117(25):6825–6836. https://doi.org/10.1182/blood-2011-02-339812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ensley HE, Tobias B, Pretus HA, McNamee RB, Jones EL, Browder IW et al (1994) NMR spectral analysis of a water-insoluble (1–>3)-beta-D-glucan isolated from Saccharomyces cerevisiae. Carbohydr Res 258:307–311. https://doi.org/10.1016/0008-6215(94)84098-9

    Article  CAS  PubMed  Google Scholar 

  6. Plato A, Willment JA, Brown GD (2013) C-type lectin-like receptors of the dectin-1 cluster: ligands and signaling pathways. Int Rev Immunol 32(2):134–156. https://doi.org/10.3109/08830185.2013.777065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Manabe N, Yamaguchi Y (2021) 3D Structural Insights into beta-Glucans and Their Binding Proteins. Int J Mol Sci. https://doi.org/10.3390/ijms22041578

    Article  PubMed  PubMed Central  Google Scholar 

  8. Miyamoto N, Mochizuki S, Sakurai K (2018) Designing an immunocyte-targeting delivery system by use of beta-glucan. Vaccine 36(1):186–189. https://doi.org/10.1016/j.vaccine.2017.11.053

    Article  CAS  PubMed  Google Scholar 

  9. Huang H, Ostroff GR, Lee CK, Specht CA, Levitz SM (2013) Characterization and optimization of the glucan particle-based vaccine platform. Clin Vaccine Immunol 20(10):1585–1591. https://doi.org/10.1128/CVI.00463-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Soto ER, Ostroff GR (2008) Characterization of multilayered nanoparticles encapsulated in yeast cell wall particles for DNA delivery. Bioconjug Chem 19(4):840–848. https://doi.org/10.1021/bc700329p

    Article  CAS  PubMed  Google Scholar 

  11. Aouadi M, Tesz GJ, Nicoloro SM, Wang M, Chouinard M, Soto E et al (2009) Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation. Nature 458(7242):1180–1184. https://doi.org/10.1038/nature07774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tesz GJ, Aouadi M, Prot M, Nicoloro SM, Boutet E, Amano SU et al (2011) Glucan particles for selective delivery of siRNA to phagocytic cells in mice. Biochem J 436(2):351–362. https://doi.org/10.1042/BJ20110352

    Article  CAS  PubMed  Google Scholar 

  13. De Marco CE, Calder PC, Roche HM (2021) beta-1,3/1,6-Glucans and Immunity: State of the Art and Future Directions. Mol Nutr Food Res 65(1):e1901071. https://doi.org/10.1002/mnfr.201901071

    Article  CAS  Google Scholar 

  14. Vetvicka V, Vannucci L, Sima P (2020) beta-glucan as a new tool in vaccine development. Scand J Immunol 91(2):e12833. https://doi.org/10.1111/sji.12833

    Article  PubMed  Google Scholar 

  15. Stier H, Ebbeskotte V, Gruenwald J (2014) Immune-modulatory effects of dietary Yeast Beta-1,3/1,6-D-glucan. Nutr J 13:38. https://doi.org/10.1186/1475-2891-13-38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang M, Kim JA, Huang AY (2018) Optimizing Tumor Microenvironment for Cancer Immunotherapy: beta-Glucan-Based Nanoparticles. Front Immunol 9:341. https://doi.org/10.3389/fimmu.2018.00341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li B, Cramer D, Wagner S, Hansen R, King C, Kakar S et al (2007) Yeast glucan particles activate murine resident macrophages to secrete proinflammatory cytokines via MyD88- and Syk kinase-dependent pathways. Clin Immunol 124(2):170–181. https://doi.org/10.1016/j.clim.2007.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ning Y, Xu D, Zhang X, Bai Y, Ding J, Feng T et al (2016) beta-glucan restores tumor-educated dendritic cell maturation to enhance antitumor immune responses. Int J Cancer 138(11):2713–2723. https://doi.org/10.1002/ijc.30002

    Article  CAS  PubMed  Google Scholar 

  19. Huang H, Ostroff GR, Lee CK, Specht CA, Levitz SM (2010) Robust stimulation of humoral and cellular immune responses following vaccination with antigen-loaded beta-glucan particles. mBio. https://doi.org/10.1128/mBio.00164-10

    Article  PubMed  PubMed Central  Google Scholar 

  20. Hong F, Yan J, Baran JT, Allendorf DJ, Hansen RD, Ostroff GR et al (2004) Mechanism by which orally administered beta-1,3-glucans enhance the tumoricidal activity of antitumor monoclonal antibodies in murine tumor models. J Immunol 173(2):797–806. https://doi.org/10.4049/jimmunol.173.2.797

    Article  CAS  PubMed  Google Scholar 

  21. Yunna C, Mengru H, Lei W, Weidong C (2020) Macrophage M1/M2 polarization. Eur J Pharmacol 877:173090. https://doi.org/10.1016/j.ejphar.2020.173090

    Article  CAS  PubMed  Google Scholar 

  22. Joffre OP, Segura E, Savina A, Amigorena S (2012) Cross-presentation by dendritic cells. Nat Rev Immunol 12(8):557–569. https://doi.org/10.1038/nri3254

    Article  CAS  PubMed  Google Scholar 

  23. Xu J, Wang H, Xu L, Chao Y, Wang C, Han X et al (2019) Nanovaccine based on a protein-delivering dendrimer for effective antigen cross-presentation and cancer immunotherapy. Biomaterials 207:1–9. https://doi.org/10.1016/j.biomaterials.2019.03.037

    Article  CAS  PubMed  Google Scholar 

  24. Waldman AD, Fritz JM, Lenardo MJ (2020) A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol 20(11):651–668. https://doi.org/10.1038/s41577-020-0306-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kaech SM, Wherry EJ, Ahmed R (2002) Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol 2(4):251–262. https://doi.org/10.1038/nri778

    Article  CAS  PubMed  Google Scholar 

  26. Warrier VU, Makandar AI, Garg M, Sethi G, Kant R, Pal JK et al (2019) Engineering anti-cancer nanovaccine based on antigen cross-presentation. Biosci Rep. https://doi.org/10.1042/BSR20193220

  27. Galluzzi L, Chan TA, Kroemer G, Wolchok JD, Lopez-Soto A (2018) The hallmarks of successful anticancer immunotherapy. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aat7807

    Article  PubMed  Google Scholar 

  28. Nobuoka D, Yoshikawa T, Takahashi M, Iwama T, Horie K, Shimomura M et al (2013) Intratumoral peptide injection enhances tumor cell antigenicity recognized by cytotoxic T lymphocytes: a potential option for improvement in antigen-specific cancer immunotherapy. Cancer Immunol Immunother 62(4):639–652. https://doi.org/10.1007/s00262-012-1366-6

    Article  CAS  PubMed  Google Scholar 

  29. Park YM, Lee SJ, Kim YS, Lee MH, Cha GS, Jung ID et al (2013) Nanoparticle-based vaccine delivery for cancer immunotherapy. Immune Netw 13(5):177–183. https://doi.org/10.4110/in.2013.13.5.177

    Article  PubMed  PubMed Central  Google Scholar 

  30. Belfiore L, Saunders DN, Ranson M, Thurecht KJ, Storm G, Vine KL (2018) Towards clinical translation of ligand-functionalized liposomes in targeted cancer therapy: Challenges and opportunities. J Control Release 277:1–13. https://doi.org/10.1016/j.jconrel.2018.02.040

    Article  CAS  PubMed  Google Scholar 

  31. Chesson CB, Huante M, Nusbaum RJ, Walker AG, Clover TM, Chinnaswamy J et al (2018) Nanoscale Peptide Self-assemblies Boost BCG-primed Cellular Immunity Against Mycobacterium tuberculosis. Sci Rep 8(1):12519. https://doi.org/10.1038/s41598-018-31089-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Liu M, Luo F, Ding C, Albeituni S, Hu X, Ma Y et al (2015) Dectin-1 Activation by a Natural Product beta-Glucan Converts Immunosuppressive Macrophages into an M1-like Phenotype. J Immunol 195(10):5055–5065. https://doi.org/10.4049/jimmunol.1501158

    Article  CAS  PubMed  Google Scholar 

  33. Kumar R, Kumar P (2019) Yeast-based vaccines: New perspective in vaccine development and application. FEMS Yeast Res. https://doi.org/10.1093/femsyr/foz007

    Article  PubMed  Google Scholar 

  34. Melssen M, Slingluff CL Jr (2017) Vaccines targeting helper T cells for cancer immunotherapy. Curr Opin Immunol 47:85–92. https://doi.org/10.1016/j.coi.2017.07.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Xie Y, Akpinarli A, Maris C, Hipkiss EL, Lane M, Kwon EK et al (2010) Naive tumor-specific CD4(+) T cells differentiated in vivo eradicate established melanoma. J Exp Med 207(3):651–667. https://doi.org/10.1084/jem.20091921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Quezada SA, Simpson TR, Peggs KS, Merghoub T, Vider J, Fan X et al (2010) Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J Exp Med 207(3):637–650. https://doi.org/10.1084/jem.20091918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ahrends T, Babala N, Xiao Y, Yagita H, van Eenennaam H, Borst J (2016) CD27 Agonism Plus PD-1 Blockade Recapitulates CD4+ T-cell Help in Therapeutic Anticancer Vaccination. Cancer Res 76(10):2921–2931. https://doi.org/10.1158/0008-5472.CAN-15-3130

    Article  CAS  PubMed  Google Scholar 

  38. Hassan SB, Sorensen JF, Olsen BN, Pedersen AE (2014) Anti-CD40-mediated cancer immunotherapy: an update of recent and ongoing clinical trials. Immunopharmacol Immunotoxicol 36(2):96–104. https://doi.org/10.3109/08923973.2014.890626

    Article  CAS  PubMed  Google Scholar 

  39. Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y et al (2012) PD-1 blockade enhances T-cell migration to tumors by elevating IFN-gamma inducible chemokines. Cancer Res 72(20):5209–5218. https://doi.org/10.1158/0008-5472.CAN-12-1187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kim HJ, Cantor H (2014) CD4 T-cell subsets and tumor immunity: the helpful and the not-so-helpful. Cancer Immunol Res 2(2):91–98. https://doi.org/10.1158/2326-6066.CIR-13-0216

    Article  CAS  PubMed  Google Scholar 

  41. Li B, Cai Y, Qi C, Hansen R, Ding C, Mitchell TC et al (2010) Orally administered particulate beta-glucan modulates tumor-capturing dendritic cells and improves antitumor T-cell responses in cancer. Clin Cancer Res 16(21):5153–5164. https://doi.org/10.1158/1078-0432.CCR-10-0820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Drokov M, Davydova Y, Popova N, Kapranov N, Starikova O, Mikhaltsova E et al (2020) High expression of granzyme B in conventional CD4+ T cells is associated with increased relapses after allogeneic stem cells transplantation in patients with hematological malignancies. Transpl Immunol. https://doi.org/10.1016/j.trim.2020.101295

    Article  PubMed  Google Scholar 

  43. Geller A, Shrestha R, Yan J (2019) Yeast-Derived beta-Glucan in Cancer: Novel Uses of a Traditional Therapeutic. Int J Mol Sci. https://doi.org/10.3390/ijms20153618

    Article  PubMed  PubMed Central  Google Scholar 

  44. Zheng B, Ren T, Huang Y, Sun K, Wang S, Bao X et al (2018) PD-1 axis expression in musculoskeletal tumors and antitumor effect of nivolumab in osteosarcoma model of humanized mouse. J Hematol Oncol 11(1):16. https://doi.org/10.1186/s13045-018-0560-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yu X, Gao R, Li Y, Zeng C (2020) Regulation of PD-1 in T cells for cancer immunotherapy. Eur J Pharmacol 881:173240. https://doi.org/10.1016/j.ejphar.2020.173240

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81672799 to C.Q.); Key Project of Jiangsu S &T Plan (BE2019651 to C.Q.); the Natural Science Foundation of Jiangsu Province (BK20200178 to D.J.); Changzhou Sci &Tech Program (CJ20210095 to Z.Z.) and the Youth Talent Sci &Tech Project of the Changzhou Commission of Health (QN202036 to L.H.).

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Authors and Affiliations

  1. State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Science, School of Life Science, Fudan University, Shanghai, 200433, China

    Liuyang He & Cui Tang

  2. Medical Research Center, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, 213003, China

    Liuyang He, Yu Bai, Lei Xia, Jie Pan, Xiao Sun, Zhichao Zhu, Jun Ding & Chunjian Qi

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  1. Liuyang He
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  2. Yu Bai
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  3. Lei Xia
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  5. Xiao Sun
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  6. Zhichao Zhu
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LH was involved in conceptualization, data curation, investigation, methodology, validation and writing—original draft. YB and LX contributed to data curation, methodology and resources. JP and XS performed methodology, data curation and software. ZZ and JD done methodology and resources. CQ and CT contributed to funding acquisition, supervision and writing—review and editing.

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Correspondence to Chunjian Qi or Cui Tang.

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He, L., Bai, Y., Xia, L. et al. Oral administration of a whole glucan particle (WGP)-based therapeutic cancer vaccine targeting macrophages inhibits tumor growth. Cancer Immunol Immunother 71, 2007–2028 (2022). https://doi.org/10.1007/s00262-021-03136-7

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