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A particulate saponin/TLR agonist vaccine adjuvant alters lymph flow and modulates adaptive immunity.

ABSTRACT: Saponins are potent and safe vaccine adjuvants, but their mechanisms of action remain incompletely understood. Here, we explored the properties of several saponin formulations, including immune-stimulatory complexes (ISCOMs) formed by the self-assembly of saponin and phospholipids in the absence or presence of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). We found that MPLA self-assembles with saponins to form particles physically resembling ISCOMs, which we termed saponin/MPLA nanoparticles (SMNP). Saponin-containing adjuvants exhibited distinctive mechanisms of action, altering lymph flow in a mast cell–dependent manner and promoting antigen entry into draining lymph nodes. SMNP was particularly effective, exhibiting even greater potency than the compositionally related adjuvant AS01_B in mice, and primed robust germinal center B cell, T_FH, and HIV tier 2 neutralizing antibodies in nonhuman primates. Together, these findings shed new light on mechanisms by which saponin adjuvants act to promote the immune response and suggest that SMNP may be a promising adjuvant in the setting of HIV, SARS-CoV-2, and other pathogens.

SUBMITTER: Silva M

PROVIDER: S-EPMC8763571 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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A particulate saponin/TLR agonist vaccine adjuvant alters lymph flow and modulates adaptive immunity.

Silva Murillo M Kato Yu Y Melo Mariane B MB Phung Ivy I Freeman Brian L BL Li Zhongming Z Roh Kangsan K Van Wijnbergen Jan W JW Watkins Hannah H Enemuo Chiamaka A CA Hartwell Brittany L BL Chang Jason Y H JYH Xiao Shuhao S Rodrigues Kristen A KA Cirelli Kimberly M KM Li Na N Haupt Sonya S Aung Aereas A Cossette Benjamin B Abraham Wuhbet W Kataria Swati S Bastidas Raiza R Bhiman Jinal J Linde Caitlyn C Bloom Nathaniel I NI Groschel Bettina B Georgeson Erik E Phelps Nicole N Thomas Ayush A Bals Julia J Carnathan Diane G DG Lingwood Daniel D Burton Dennis R DR Alter Galit G Padera Timothy P TP Belcher Angela M AM Schief William R WR Silvestri Guido G Ruprecht Ruth M RM Crotty Shane S Irvine Darrell J DJ

Science immunology 20211203 66

Saponins are potent and safe vaccine adjuvants, but their mechanisms of action remain incompletely understood. Here, we explored the properties of several saponin formulations, including immune-stimulatory complexes (ISCOMs) formed by the self-assembly of saponin and phospholipids in the absence or presence of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). We found that MPLA self-assembles with saponins to form particles physically resembling ISCOMs, which we termed saponin/MPLA ...[more]

PMID: 34860581

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Project description:BackgroundOsteosarcoma (OS) is the most common primary bone tumor in children and adolescent. Surgery and multidrug chemotherapy are the standard of treatment achieving 60-70% of event-free survival for localized disease at diagnosis. However, for metastatic disease, the prognosis is dismal. Exploiting immune system activation in the setting of such unfavorable mesenchymal tumors represents a new therapeutic challenge.MethodsIn immune competent OS mouse models bearing two contralateral lesions, we tested the efficacy of intralesional administration of a TLR9 agonist against the treated and not treated contralateral lesion evaluating abscopal effect. Multiparametric flow cytometry was used to evaluate changes of the tumor immune microenviroment. Experiments in immune-deficient mice allowed the investigation of the role of adaptive T cells in TLR9 agonist effects, while T cell receptor sequencing was used to assess the expansion of specific T cell clones.ResultsTLR9 agonist strongly impaired the growth of locally-treated tumors and its therapeutic effect also extended to the contralateral, untreated lesion. Multiparametric flow cytometry showed conspicuous changes in the immune landscape of the OS immune microenvironment upon TLR9 engagement, involving a reduction in M2-like macrophages, paralleled by increased infiltration of dendritic cells and activated CD8 T cells in both lesions. Remarkably, CD8 T cells were needed for the induction of the abscopal effect, whereas they were not strictly necessary for halting the growth of the treated lesion. T cell receptor (TCR) sequencing of tumor infiltrating CD8 T cells showed the expansion of specific TCR clones in the treated tumors and, remarkably, their selected representation in the contralateral untreated lesions, providing the first evidence of the rewiring of tumor-associated T cell clonal architectures.ConclusionsOverall these data indicate that the TLR9 agonist acts as an in situ anti-tumor vaccine, activating an innate immune response sufficient to suppress local tumor growth while inducing a systemic adaptive immunity with selective expansion of CD8 T cell clones, which are needed for the abscopal effect.

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A particulate saponin/TLR agonist vaccine adjuvant alters lymph flow and modulates adaptive immunity.

Publications

A particulate saponin/TLR agonist vaccine adjuvant alters lymph flow and modulates adaptive immunity.

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