RGD Reference Report - Toll-like receptor 4 gene polymorphism influences dendritic cell in vitro function and clinical outcomes in vaccinated melanoma patients. - Rat Genome Database

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Toll-like receptor 4 gene polymorphism influences dendritic cell in vitro function and clinical outcomes in vaccinated melanoma patients.

Authors: Tittarelli, A  Gonzalez, FE  Pereda, C  Mora, G  Munoz, L  Saffie, C  Garcia, T  Diaz, D  Falcon, C  Hermoso, M  Lopez, MN  Salazar-Onfray, F 
Citation: Tittarelli A, etal., Cancer Immunol Immunother. 2012 Nov;61(11):2067-77. doi: 10.1007/s00262-012-1268-7. Epub 2012 May 3.
RGD ID: 7777154
Pubmed: PMID:22552381   (View Abstract at PubMed)
DOI: DOI:10.1007/s00262-012-1268-7   (Journal Full-text)

Toll-like receptor 4 (TLR4) is expressed on dendritic cells (DCs), sensing environmental danger molecules that induce their activation and maturation. Recently, we reported a method for the production of therapeutic DCs against melanoma, called tumor antigen-presenting cells (TAPCells), using a heat-shocked allogeneic melanoma cell lysate (TRIMEL) as an activation factor and antigen provider. Since TRIMEL contains endogenous TLR4 ligands, we evaluated the role of TLR4 in TAPCells differentiation by antibody neutralization and the association of a Tlr4 polymorphism (896A/G) (Asp299Gly), determined by PCR-RFLP, with the in vitro activation capacity and the clinical outcome of TAPCells-vaccinated patients. Antibody blocking of monocyte TLR4 inhibited surface expression, determined by flow cytometry, of the major histocompatibility complex class I, CCR7, CD80, CD83 and CD86 on TAPCells, reduced interleukin (IL)-6 and tumor necrosis factor -alpha gene expression evaluated by qRT-PCR, and also inhibited the TAPCells-mediated interferon-gamma (IFN-gamma) secretion of melanoma-specific CD8(+) T cells determined by ELISpot (p < 0.01). Moreover, CD8(+) T-cell activation capacity was significantly reduced in TAPCells bearing the TLR4 Asp299Gly receptor (p < 0.05). Finally, TAPCells-vaccinated stage-IV melanoma patients bearing the Tlr4 896G allele showed a shortened post-therapy median survival rate compared with those carrying the Tlr4 896A allele (p < 0.05; log-rank test). Our results indicate that TLR4 is a key receptor for the tumor lysate-mediated in vitro generation of clinically efficient antigen-presenting cells. Further analysis of patients included in different vaccine protocols is necessary for definitively establishing a role for TLR4 polymorphism in clinical responses.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
melanoma  IAGP 7777154DNA:polymorphisms:exons:p.D299G (896A>G)(human and )RGD 
melanoma  ISOTLR4 (Homo sapiens)7777154; 7777154DNA:polymorphisms:exons:p.D299G (896A>G)(human and )RGD 

Objects Annotated

Genes (Rattus norvegicus)
Tlr4  (toll-like receptor 4)

Genes (Mus musculus)
Tlr4  (toll-like receptor 4)

Genes (Homo sapiens)
TLR4  (toll like receptor 4)


Additional Information