A simple, clinically relevant therapeutic vaccine shows long-term protection in an aggressive, delayed-treatment B lymphoma model

Pradhan, Pallab; Leleux, Jardin; Liu, Jiaying; Roy, Krishnendu

doi:10.1172/jci.insight.92522

Cited by 6 publications

(2 citation statements)

References 38 publications

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“…The PLPs are poly(lactic-co-glycolic acid) (PLGA) particles with branched polyethylenimine (bPEI) conjugated to the particle surface. We have extensively published on the synthesis, characterization, and delivery of single and multiple adjuvants and antigens on these PLPs, both in vitro and in vivo ( 19 , 31 , 33 , 34 ). For the current studies, MPLA adjuvant was first encapsulated into the particle during double-emulsion, solvent evaporation–based synthesis.…”

Section: Resultsmentioning

confidence: 99%

TRAF6-IRF5 kinetics, TRIF, and biophysical factors drive synergistic innate responses to particle-mediated MPLA-CpG co-presentation

et al. 2021

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Innate immune responses to pathogens are driven by co-presentation of multiple pathogen-associated molecular patterns (PAMPs). Combinations of PAMPs can trigger synergistic immune responses, but the underlying molecular mechanisms of synergy are poorly understood. Here, we used synthetic particulate carriers co-loaded with monophosphoryl lipid A (MPLA) and CpG as pathogen-like particles (PLPs) to dissect the signaling pathways responsible for dual adjuvant immune responses. PLP-based co-delivery of MPLA and CpG to GM-CSF–driven mouse bone marrow–derived antigen-presenting cells (BM-APCs) elicited synergistic interferon-β (IFN-β) and interleukin-12p70 (IL-12p70) responses, which were strongly influenced by the biophysical properties of PLPs. Mechanistically, we found that MyD88 and interferon regulatory factor 5 (IRF5) were necessary for IFN-β and IL-12p70 production, while TRIF signaling was required for the synergistic response. Both the kinetics and magnitude of downstream TRAF6 and IRF5 signaling drove the synergy. These results identify the key mechanisms of synergistic Toll-like receptor 4 (TLR4)–TLR9 co-signaling in mouse BM-APCs and underscore the critical role of signaling kinetics and biophysical properties on the integrated response to combination adjuvants.

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Section: Resultsmentioning

confidence: 99%

TRAF6-IRF5 kinetics, TRIF, and biophysical factors drive synergistic innate responses to particle-mediated MPLA-CpG co-presentation

et al. 2021

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show abstract

“…The PLPs are PLGA particles with branched polyethylenimine (PEI) conjugated to the particle surface. We have extensively published on the synthesis, characterization, and delivery of single and multiple adjuvants and antigens on these PLPs, both in vitro and in vivo (19,31,33,34). For the current studies, MPLA adjuvant was first encapsulated into the particle during double-emulsion, solvent-evaporation based synthesis.…”

Section: Density Of Cpg Presentation But Not Particle Size Influencmentioning

confidence: 99%

TRAF6-IRF5 kinetics, TRIF, and biophysical factors drive synergistic innate responses to particle-mediated MPLA-CpG co-presentation

Pradhan

Toy

Jhita

et al. 2020

Preprint

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Innate immune responses to pathogens are driven by co-presentation of multiple pathogen-associated molecular patterns (PAMPs). PAMPs and PAMP-analogs are also used as immune-adjuvants to enhance vaccine efficacy by activating various Pattern Recognition Receptors (PRRs), like Toll-like receptors (TLRs). Various combinations of PAMP adjuvants can trigger synergistic immune responses, but the underlying molecular mechanisms driving that synergy are poorly understood. Here, we used synthetic particulate carriers co-loaded with MPLA (TLR4-adjuvant) and CpG (TLR9-adjuvant) as pathogen-like particles (PLPs) to dissect the signaling pathways responsible for the integrated, dual-adjuvant immune response. PLP-based co-presentation of MPLA and CpG to mouse bone marrow derived antigen-presenting cells (BM-APCs) elicited synergistic Type-I Interferon (IFN-beta) and IL-12p70 responses, which were strongly influenced by the biophysical properties of PLPs. Mechanistically, we found that the adapter protein MyD88 and the Interferon-Regulatory-Factor-5 (IRF-5), but not the canonical factors IRF-3 or IRF-7, were necessary for production of both IFN-beta and IL12p70. TRIF signaling was required to elicit the synergistic response; the absence of TRIF abolished synergy. Importantly, both the kinetics and magnitude of downstream TRAF6 and IRF5 signaling (TRIF-TRAF-IRF5 pathway kinetics) drove the observed synergy. These results identify not only the key signaling mechanism that cooperates to generate a combinatorial response to MPLA-CpG dual engagement in BM-APCs, but they also underscore the critical role that signaling kinetics and biophysical presentation plays in integrated responses to combination adjuvants.

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Invariant NKT cell-augmented GM-CSF-secreting tumor vaccine is effective in advanced prostate cancer model

Varghese

Lynch

Vriend

et al. 2022

Cancer Immunol Immunother

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A simple, clinically relevant therapeutic vaccine shows long-term protection in an aggressive, delayed-treatment B lymphoma model

Cited by 6 publications

References 38 publications

TRAF6-IRF5 kinetics, TRIF, and biophysical factors drive synergistic innate responses to particle-mediated MPLA-CpG co-presentation

TRAF6-IRF5 kinetics, TRIF, and biophysical factors drive synergistic innate responses to particle-mediated MPLA-CpG co-presentation

TRAF6-IRF5 kinetics, TRIF, and biophysical factors drive synergistic innate responses to particle-mediated MPLA-CpG co-presentation

Invariant NKT cell-augmented GM-CSF-secreting tumor vaccine is effective in advanced prostate cancer model

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