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1.
Nature ; 515(7528): 568-71, 2014 Nov 27.
Article in English | MEDLINE | ID: mdl-25428505

ABSTRACT

Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8(+) T cells (termed adaptive immune resistance). Here we show that pre-existing CD8(+) T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8(+) T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8(+) T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.


Subject(s)
Adaptive Immunity/immunology , CD8-Positive T-Lymphocytes/immunology , Immunotherapy , Melanoma/therapy , Models, Biological , Aged , Aged, 80 and over , Biomarkers , CD8-Positive T-Lymphocytes/cytology , Cell Proliferation , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Melanoma/diagnosis , Melanoma/immunology , Melanoma/pathology , Middle Aged , Multivariate Analysis , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/immunology , Treatment Outcome
2.
Arthritis Rheum ; 60(4): 1085-95, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19333953

ABSTRACT

OBJECTIVE: Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder, with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in terms of the pathogenesis of SLE. STAT-1 and STAT-4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for involvement in SLE susceptibility. METHODS: Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 on chromosome 2 were genotyped using the Illumina platform, as part of an extensive association study in a large collection of 9,923 lupus patients and control subjects from different racial groups. DNA samples were obtained from the peripheral blood of patients with SLE and control subjects. Principal components analyses and population-based case-control association analyses were performed, and the P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated. RESULTS: We observed strong genetic associations with SLE and multiple SNPs located within STAT4 in different ethnic groups (Fisher's combined P = 7.02 x 10(-25)). In addition to strongly confirming the previously reported association in the third intronic region of this gene, we identified additional haplotypic association across STAT4 and, in particular, a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to its proximity to STAT4. CONCLUSION: Our findings indicate that STAT4 is likely to be a crucial component in SLE pathogenesis in multiple racial groups. Knowledge of the functional effects of this association, when they are revealed, might improve our understanding of the disease and provide new therapeutic targets.


Subject(s)
Lupus Erythematosus, Systemic/ethnology , Lupus Erythematosus, Systemic/genetics , Racial Groups/statistics & numerical data , STAT4 Transcription Factor/genetics , Black or African American/statistics & numerical data , Asian/statistics & numerical data , Asian People/statistics & numerical data , Female , Genetic Predisposition to Disease/ethnology , Haplotypes , Hispanic or Latino/statistics & numerical data , Humans , Male , Polymorphism, Single Nucleotide , Risk Factors , STAT1 Transcription Factor/genetics , United States/epidemiology , White People/statistics & numerical data
3.
J Immunol ; 171(3): 1564-71, 2003 Aug 01.
Article in English | MEDLINE | ID: mdl-12874250

ABSTRACT

We have developed novel genetically lupus-prone (NZB x NZW)F(1)-derived congenic New Zealand mixed (NZM) 2328 lines, which are either Stat4- or Stat6-deficient. Our studies show that the deficiency of Stat4 and Stat6 significantly alters the phenotype of the lupus-like disease in NZM 2328 congenic mice. Specifically, Stat4-deficient NZM mice develop accelerated nephritis and increased mortality in the absence of high levels of autoantibodies including anti-dsDNA Abs, and in the presence of relatively reduced levels of IFN-gamma. In contrast, Stat6-deficient NZM mice display a significant reduction in incidence of kidney disease, with a dramatic increase in survival, despite the presence of high levels of anti-dsDNA Abs. The lack of correlation between levels of these autoantibodies and kidney disease raises the question of the direct cause-effect relationships between the presence of autoantibodies and kidney disease. Furthermore, these results also question the apparent equation of the effect of Stat deficiency with loss of secretion or response to particular cytokines.


Subject(s)
DNA-Binding Proteins/physiology , Lupus Nephritis/genetics , Lupus Nephritis/immunology , Trans-Activators/physiology , Animals , Cells, Cultured , Crosses, Genetic , Cytokines/biosynthesis , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Female , Gene Deletion , Genetic Predisposition to Disease , Lupus Nephritis/mortality , Mice , Mice, Congenic , Mice, Inbred C57BL , Mice, Inbred NZB , Mice, Knockout , STAT4 Transcription Factor , STAT6 Transcription Factor , Species Specificity , Th1 Cells/immunology , Th1 Cells/metabolism , Th2 Cells/immunology , Th2 Cells/metabolism , Trans-Activators/deficiency , Trans-Activators/genetics
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