Engaging Natural Killer T Cells as ‘Universal Helpers’ for Vaccination

Speir, Mary; Hermans, Ian F.; Weinkove, Robert

doi:10.1007/s40265-016-0675-z

Cited by 30 publications

(29 citation statements)

References 207 publications

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“…Abnormal cell cycle is a hallmark of cancer. Targeting this pathway has already shown a promise in treating breast cancer, and several drugs targeting cell cycle have been approved by FDA 42 , 43 . Recent studies in cell cycle indicated that the interaction among cyclins, CDKs and cyclin-dependent kinase inhibitors (CKIs) plays a fundamental role in cell cycle progression 13 , 44 , 45 .…”

Section: Discussionmentioning

confidence: 99%

The antipsychotic agent trifluoperazine hydrochloride suppresses triple-negative breast cancer tumor growth and brain metastasis by inducing G0/G1 arrest and apoptosis

et al. 2018

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Women with aggressive triple-negative breast cancer (TNBC) are at high risk of brain metastasis, which has no effective therapeutic option partially due to the poor penetration of drugs across the blood−brain barrier. Trifluoperazine (TFP) is an approved antipsychotic drug with good bioavailability in brain and had shown anticancer effect in several types of cancer. It drives us to investigate its activities to suppress TNBC, especially the brain metastasis. In this study, we chose three TNBC cell lines MDA-MB-468, MDA-MB-231, and 4T1 to assess its anticancer activities along with the possible mechanisms. In vitro, it induced G0/G1 cell cycle arrest via decreasing the expression of both cyclinD1/CDK4 and cyclinE/CDK2, and stimulated mitochondria-mediated apoptosis. In vivo, TFP suppressed the growth of subcutaneous xenograft tumor and brain metastasis without causing detectable side effects. Importantly, it prolonged the survival of mice bearing brain metastasis. Immunohistochemical analysis of Ki67 and cleaved caspase-3 indicated TFP could suppress the growth and induce apoptosis of cancer cells in vivo. Taken together, TFP might be a potential available drug for treating TNBC with brain metastasis, which urgently needs novel treatment options.

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Section: Discussionmentioning

confidence: 99%

The antipsychotic agent trifluoperazine hydrochloride suppresses triple-negative breast cancer tumor growth and brain metastasis by inducing G0/G1 arrest and apoptosis

et al. 2018

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“…Invariant natural killer T (iNKT) cells are a unique subsets of T cells that recognize conserved microbial lipid antigens presented by CD1d (non‐polymorphic MHC class I‐like molecules) rather than peptides associated with classical MHC class I or II molecules. Recent studies have demonstrated that these cells also possess immunological functions similar to those of traditional CD4+T helper (Th) cells . Once activated, iNKT cells release large quantities of various cytokines, which may help B cells to proliferate and undergo antibody class switching and affinity maturation .…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies have demonstrated that these cells also possess immunological functions similart ot hose of traditional CD4 + Th elper (Th) cells. [7] Once activated, iNKT cells release large quantities of various cytokines, which may help B cells to proliferate and undergo antibody class switching and affinity maturation. [8] This unique property prompted scientists to developp otent vaccines bearing the iNKT cell agonist a-galactosylceramide (aGalCer) or its analogues as adjuvants.…”

mentioning

confidence: 99%

Liposomal Antitumor Vaccines Targeting Mucin 1 Elicit a Lipid‐Dependent Immunodominant Response

Zou

Chen

et al. 2019

Chemistry An Asian Journal

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The tumor‐associated antigen mucin 1 (MUC1) has been pursued as an attractive target for cancer immunotherapy, but the poor immunogenicity of the endogenous antigen hinders the development of vaccines capable of inducing effective anti‐MUC1 immunodominant responses. Herein, we prepared synthetic anti‐MUC1 vaccines in which the hydrophilic MUC1 antigen was N‐terminally conjugated to one or two palmitoyl lipid chains (to form amphiphilic Pam‐MUC1 or Pam2‐MUC1). These amphiphilic lipid‐tailed MUC1 antigens were self‐assembled into liposomes containing the NKT cell agonist αGalCer as an adjuvant. The lipid‐conjugated antigens reshaped the physical and morphological properties of liposomal vaccines. Promising results showed that the anti‐MUC1 IgG antibody titers induced by the Pam2‐MUC1 vaccine were more than 30‐ and 190‐fold higher than those induced by the Pam‐MUC1 vaccine and the MUC1 vaccine without lipid tails, respectively. Similarly, vaccines with the TLR1/2 agonist Pam3CSK4 as an adjuvant also induced conjugated lipid‐dependent immunological responses. Moreover, vaccines with the αGalCer adjuvant induced significantly higher titers of IgG antibodies than vaccines with the Pam3CSK4 adjuvant. Therefore, the non‐covalent assembly of the amphiphilic lipo‐MUC1 antigen and the NKT cell agonist αGalCer as a glycolipid adjuvant represent a synthetically simple but immunologically effective approach for the development of anti‐MUC1 cancer vaccines.

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“…This help depends on peptide and glycolipid presentation by the same APC, and in vivo requires an interaction between CD40 and CD40L 18 , 19 . Potential advantages of exploiting NKT rather than conventional CD4 + T cell help in a clinical context include avoiding the need to select adjuvants according to MHC class II expression 20 , and eliciting a CD8 + T cell response with a distinct chemokine receptor profile 21 , 22 . In mouse models, NKT cell activation at the time of vaccination or infection promotes virus-specific CD8 + T cell memory 23 , 24 .…”

Section: Introductionmentioning

confidence: 99%

Glycolipid-peptide conjugate vaccines enhance CD8+ T cell responses against human viral proteins

Speir

Authier-Hall

Brooks

et al. 2017

Sci Rep

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An important goal of vaccination against viruses and virus-driven cancers is to elicit cytotoxic CD8+ T cells specific for virus-derived peptides. CD8+ T cell responses can be enhanced by engaging help from natural killer T (NKT) cells. We have produced synthetic vaccines that induce strong peptide-specific CD8+ T cell responses in vivo by incorporating an NKT cell-activating glycolipid. Here we examine the effect of a glycolipid-peptide conjugate vaccine incorporating an NKT cell-activating glycolipid linked to an MHC class I-restricted peptide from a viral antigen in human peripheral blood mononuclear cells. The vaccine induces CD1d-dependent activation of human NKT cells following enzymatic cleavage, activates human dendritic cells in an NKT-cell dependent manner, and generates a pool of activated antigen-specific CD8+ T cells with cytotoxic potential. Compared to unconjugated peptide, the vaccine upregulates expression of genes encoding interferon-γ, CD137 and granzyme B. A similar vaccine incorporating a peptide from the clinically-relevant human papilloma virus (HPV) 16 E7 oncoprotein induces cytotoxicity against peptide-expressing targets in vivo, and elicits a better antitumor response in a model of E7-expressing lung cancer than its unconjugated components. Glycolipid-peptide conjugate vaccines may prove useful for the prevention or treatment of viral infections and tumors that express viral antigens.

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Engaging Natural Killer T Cells as ‘Universal Helpers’ for Vaccination

Cited by 30 publications

References 207 publications

The antipsychotic agent trifluoperazine hydrochloride suppresses triple-negative breast cancer tumor growth and brain metastasis by inducing G0/G1 arrest and apoptosis

The antipsychotic agent trifluoperazine hydrochloride suppresses triple-negative breast cancer tumor growth and brain metastasis by inducing G0/G1 arrest and apoptosis

Liposomal Antitumor Vaccines Targeting Mucin 1 Elicit a Lipid‐Dependent Immunodominant Response

Glycolipid-peptide conjugate vaccines enhance CD8+ T cell responses against human viral proteins

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