Saponin-based Adjuvants Induce Cross-presentation in Dendritic Cells by Intracellular Lipid Body Formation

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Nov 8

PMID 27819292

Citations 56

Authors

Martijn H den Brok

Christian Bull

Melissa Wassink

Annemarie M de Graaf

Jori A Wagenaars

Marthe Minderman

Mayank Thakur

Sebastian Amigorena

Eric O Rijke

Carla C Schrier

Gosse J Adema

Affiliations

Soon will be listed here.

Abstract

Saponin-based adjuvants (SBAs) are being used in animal and human (cancer) vaccines, as they induce protective cellular immunity. Their adjuvant potency is a factor of inflammasome activation and enhanced antigen cross-presentation by dendritic cells (DCs), but how antigen cross-presentation is induced is not clear. Here we show that SBAs uniquely induce intracellular lipid bodies (LBs) in the CD11b+ DC subset in vitro and in vivo. Using genetic and pharmacological interference in models for vaccination and in situ tumour ablation, we demonstrate that LB induction is causally related to the saponin-dependent increase in cross-presentation and T-cell activation. These findings link adjuvant activity to LB formation, aid the application of SBAs as a cancer vaccine component, and will stimulate development of new adjuvants enhancing T-cell-mediated immunity.

Citing Articles

Saponin-based adjuvant uptake and induction of antigen cross-presentation by CD11b+ dendritic cells and macrophages.

Huis In t Veld L, Cornelissen L, van den Bogaard L, Ansems M, Ho N, Adema G NPJ Vaccines. 2025; 10(1):15.

PMID: 39843492 PMC: 11754886. DOI: 10.1038/s41541-024-01056-y.

Plant Cell Culture-Derived Saponin Adjuvant Enhances Immune Response Against a Stabilized Human Metapneumovirus Pre-Fusion Vaccine Candidate.

Swart M, Allen J, Reed B, Izquierdo Gil A, Verspuij J, Schmit-Tillemans S Vaccines (Basel). 2025; 12(12.

PMID: 39772095 PMC: 11728754. DOI: 10.3390/vaccines12121435.

Modulation of antigen delivery and lymph node activation in nonhuman primates by saponin adjuvant saponin/monophosphoryl lipid A nanoparticle.

Yousefpour P, Zhang Y, Maiorino L, Melo M, Arainga Ramirez M, Kumarapperuma S PNAS Nexus. 2024; 3(12):pgae529.

PMID: 39677368 PMC: 11645456. DOI: 10.1093/pnasnexus/pgae529.

Modulation of antigen delivery and lymph node activation in non-human primates by saponin adjuvant SMNP.

Yousefpour P, Zhang Y, Maiorino L, Melo M, Arainga Ramirez M, Kumarapperuma S bioRxiv. 2024; .

PMID: 39253464 PMC: 11383317. DOI: 10.1101/2024.08.28.608716.

Development of semisynthetic saponin immunostimulants.

Bai D, Kim H, Wang P Med Chem Res. 2024; 33(8):1292-1306.

PMID: 39132259 PMC: 11315725. DOI: 10.1007/s00044-024-03227-x.

References

Kotsias F, Hoffmann E, Amigorena S, Savina A . Reactive oxygen species production in the phagosome: impact on antigen presentation in dendritic cells. Antioxid Redox Signal. 2012; 18(6):714-29. DOI: 10.1089/ars.2012.4557. View

Nicholaou T, Ebert L, Davis I, McArthur G, Jackson H, Dimopoulos N . Regulatory T-cell-mediated attenuation of T-cell responses to the NY-ESO-1 ISCOMATRIX vaccine in patients with advanced malignant melanoma. Clin Cancer Res. 2009; 15(6):2166-73. DOI: 10.1158/1078-0432.CCR-08-2484. View

den Brok M, Nierkens S, Wagenaars J, Ruers T, Schrier C, Rijke E . Saponin-based adjuvants create a highly effective anti-tumor vaccine when combined with in situ tumor destruction. Vaccine. 2011; 30(4):737-44. DOI: 10.1016/j.vaccine.2011.11.080. View

Cox R, Pedersen G, Madhun A, Svindland S, Saevik M, Breakwell L . Evaluation of a virosomal H5N1 vaccine formulated with Matrix M™ adjuvant in a phase I clinical trial. Vaccine. 2011; 29(45):8049-59. DOI: 10.1016/j.vaccine.2011.08.042. View

Poulin L, Reyal Y, Uronen-Hansson H, Schraml B, Sancho D, Murphy K . DNGR-1 is a specific and universal marker of mouse and human Batf3-dependent dendritic cells in lymphoid and nonlymphoid tissues. Blood. 2012; 119(25):6052-62. DOI: 10.1182/blood-2012-01-406967. View

Krahmer N, Guo Y, Farese Jr R, Walther T . SnapShot: Lipid Droplets. Cell. 2009; 139(5):1024-1024.e1. DOI: 10.1016/j.cell.2009.11.023. View

Weng A, Thakur M, von Mallinckrodt B, Beceren-Braun F, Gilabert-Oriol R, Wiesner B . Saponins modulate the intracellular trafficking of protein toxins. J Control Release. 2012; 164(1):74-86. DOI: 10.1016/j.jconrel.2012.10.002. View

van den Bijgaart R, Eikelenboom D, Hoogenboom M, Futterer J, den Brok M, Adema G . Thermal and mechanical high-intensity focused ultrasound: perspectives on tumor ablation, immune effects and combination strategies. Cancer Immunol Immunother. 2016; 66(2):247-258. PMC: 5281669. DOI: 10.1007/s00262-016-1891-9. View

Gocze P, Freeman D . Factors underlying the variability of lipid droplet fluorescence in MA-10 Leydig tumor cells. Cytometry. 1994; 17(2):151-8. DOI: 10.1002/cyto.990170207. View

10.

Naik S, Proietto A, Wilson N, Dakic A, Schnorrer P, Fuchsberger M . Cutting edge: generation of splenic CD8+ and CD8- dendritic cell equivalents in Fms-like tyrosine kinase 3 ligand bone marrow cultures. J Immunol. 2005; 174(11):6592-7. DOI: 10.4049/jimmunol.174.11.6592. View

11.

Merad M, Sathe P, Helft J, Miller J, Mortha A . The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol. 2013; 31:563-604. PMC: 3853342. DOI: 10.1146/annurev-immunol-020711-074950. View

12.

Paul A, Chang B, Li L, Yechoor V, Chan L . Deficiency of adipose differentiation-related protein impairs foam cell formation and protects against atherosclerosis. Circ Res. 2008; 102(12):1492-501. PMC: 2773502. DOI: 10.1161/CIRCRESAHA.107.168070. View

13.

Lutz M, Kukutsch N, OGILVIE A, Rossner S, Koch F, Romani N . An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods. 1999; 223(1):77-92. DOI: 10.1016/s0022-1759(98)00204-x. View

14.

Karttunen J, Sanderson S, Shastri N . Detection of rare antigen-presenting cells by the lacZ T-cell activation assay suggests an expression cloning strategy for T-cell antigens. Proc Natl Acad Sci U S A. 1992; 89(13):6020-4. PMC: 402130. DOI: 10.1073/pnas.89.13.6020. View

15.

Taylor G, Collazo C, Yap G, Nguyen K, Gregorio T, TAYLOR L . Pathogen-specific loss of host resistance in mice lacking the IFN-gamma-inducible gene IGTP. Proc Natl Acad Sci U S A. 2000; 97(2):751-5. PMC: 15402. DOI: 10.1073/pnas.97.2.751. View

16.

Schnurr M, Orban M, Robson N, Shin A, Braley H, Airey D . ISCOMATRIX adjuvant induces efficient cross-presentation of tumor antigen by dendritic cells via rapid cytosolic antigen delivery and processing via tripeptidyl peptidase II. J Immunol. 2009; 182(3):1253-9. DOI: 10.4049/jimmunol.182.3.1253. View

17.

Wan H, Melo R, Jin Z, Dvorak A, Weller P . Roles and origins of leukocyte lipid bodies: proteomic and ultrastructural studies. FASEB J. 2006; 21(1):167-78. PMC: 2715426. DOI: 10.1096/fj.06-6711com. View

18.

Klein O, Davis I, McArthur G, Chen L, Haydon A, Parente P . Low-dose cyclophosphamide enhances antigen-specific CD4(+) T cell responses to NY-ESO-1/ISCOMATRIX™ vaccine in patients with advanced melanoma. Cancer Immunol Immunother. 2015; 64(4):507-18. PMC: 11029160. DOI: 10.1007/s00262-015-1656-x. View

19.

Maraskovsky E, Sjolander S, Drane D, Schnurr M, Le T, Mateo L . NY-ESO-1 protein formulated in ISCOMATRIX adjuvant is a potent anticancer vaccine inducing both humoral and CD8+ t-cell-mediated immunity and protection against NY-ESO-1+ tumors. Clin Cancer Res. 2004; 10(8):2879-90. DOI: 10.1158/1078-0432.ccr-03-0245. View

20.

Duewell P, Kisser U, Heckelsmiller K, Hoves S, Stoitzner P, Koernig S . ISCOMATRIX adjuvant combines immune activation with antigen delivery to dendritic cells in vivo leading to effective cross-priming of CD8+ T cells. J Immunol. 2011; 187(1):55-63. PMC: 4285562. DOI: 10.4049/jimmunol.1004114. View