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1.
Nat Immunol ; 23(1): 50-61, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34853448

RESUMEN

NP105-113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105-113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP105-113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP105-113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP105-113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design.


Asunto(s)
Antígeno HLA-B7/inmunología , Epítopos Inmunodominantes/inmunología , Proteínas de la Nucleocápside/inmunología , SARS-CoV-2/inmunología , Linfocitos T Citotóxicos/inmunología , Anciano , Secuencia de Aminoácidos , Anticuerpos Antivirales/inmunología , Afinidad de Anticuerpos/inmunología , COVID-19/inmunología , COVID-19/patología , Línea Celular Transformada , Femenino , Perfilación de la Expresión Génica , Humanos , Memoria Inmunológica/inmunología , Masculino , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos T/inmunología , Índice de Severidad de la Enfermedad , Virus Vaccinia/genética , Virus Vaccinia/inmunología , Virus Vaccinia/metabolismo
2.
Br J Cancer ; 124(10): 1661-1669, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33723392

RESUMEN

BACKGROUND: Immune checkpoint blockers (ICBs) activate CD8+ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear. METHODS: Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab-sICB) or combination (nivolumab and ipilimumab-cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8+ T cells was sequenced and differential gene expression according to irAE development assessed. RESULTS: 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9-33.4) versus not-reached (P = 2.8 × 10-6). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8+ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment. CONCLUSIONS: Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.


Asunto(s)
Enfermedades Autoinmunes/inducido químicamente , Linfocitos T CD8-positivos/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Melanoma/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/genética , Autoinmunidad/efectos de los fármacos , Autoinmunidad/genética , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/efectos adversos , Masculino , Melanoma/inmunología , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Supervivencia sin Progresión , Estudios Retrospectivos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Análisis de Supervivencia , Transcriptoma/efectos de los fármacos , Transcriptoma/inmunología , Resultado del Tratamiento , Reino Unido/epidemiología
3.
J Immunother Cancer ; 12(4)2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38663935

RESUMEN

We describe three cases of critical acute myositis with myocarditis occurring within 22 days of each other at a single institution, all within 1 month of receiving the initial cycle of the anti-PD-1 drug pembrolizumab. Analysis of T cell receptor repertoires from peripheral blood and tissues revealed a high degree of clonal expansion and public clones between cases, with several T cell clones expanded within the skeletal muscle putatively recognizing viral epitopes. All patients had recently received a COVID-19 mRNA booster vaccine prior to treatment and were positive for SARS-CoV2 Spike antibody. In conclusion, we report a series of unusually severe myositis and myocarditis following PD-1 blockade and the COVID-19 mRNA vaccination.


Asunto(s)
Anticuerpos Monoclonales Humanizados , COVID-19 , Miocarditis , Miositis , SARS-CoV-2 , Anciano , Femenino , Humanos , Masculino , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , COVID-19/prevención & control , COVID-19/inmunología , Vacunas contra la COVID-19/efectos adversos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Miocarditis/inducido químicamente , Miositis/inducido químicamente , SARS-CoV-2/inmunología , Vacunación/efectos adversos , Anciano de 80 o más Años
4.
Nat Commun ; 13(1): 4073, 2022 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-35835762

RESUMEN

Natural Killer cells are innate lymphocytes with central roles in immunosurveillance and are implicated in autoimmune pathogenesis. The degree to which regulatory variants affect Natural Killer cell gene expression is poorly understood. Here we perform expression quantitative trait locus mapping of negatively selected Natural Killer cells from a population of healthy Europeans (n = 245). We find a significant subset of genes demonstrate expression quantitative trait loci specific to Natural Killer cells and these are highly informative of human disease, in particular autoimmunity. A Natural Killer cell transcriptome-wide association study across five common autoimmune diseases identifies further novel associations at 27 genes. In addition to these cis observations, we find novel master-regulatory regions impacting expression of trans gene networks at regions including 19q13.4, the Killer cell Immunoglobulin-like Receptor region, GNLY, MC1R and UVSSA. Our findings provide new insights into the unique biology of Natural Killer cells, demonstrating markedly different expression quantitative trait loci from other immune cells, with implications for disease mechanisms.


Asunto(s)
Enfermedades Autoinmunes , Transcriptoma , Enfermedades Autoinmunes/genética , Autoinmunidad/genética , Proteínas Portadoras , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Células Asesinas Naturales , Polimorfismo de Nucleótido Simple
5.
Nat Med ; 28(12): 2592-2600, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36526722

RESUMEN

Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to IL7. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 expression, which independently associates with irAE risk, divergent immunoglobulin expression and more B cell receptor mutations. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB-induced CD8+ T cell subset responses, skewing of T cell clonality and greater proportional repertoire occupancy by large clones. Finally, analysis of TCGA data suggests that risk allele carriers independently have improved melanoma survival. These observations highlight key roles for B cells and IL-7 in both ICB response and toxicity and clinical outcomes in melanoma.


Asunto(s)
Interleucina-7 , Melanoma , Humanos , Interleucina-7/genética , Interleucina-7/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Melanoma/tratamiento farmacológico , Melanoma/genética , Linfocitos T CD8-positivos , Variación Genética
6.
Sci Immunol ; 6(64): eabj8825, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34597125

RESUMEN

The antitumor action of immune checkpoint blockade (ICB) is primarily mediated by CD8+ T cells. How sensitivity to ICB varies across CD8+ T cell subsets and clonotypes and the relationship of these with clinical outcome is unclear. To explore this, we used single-cell V(D)J and RNA-sequencing to track gene expression changes elicited by ICB across individual peripheral CD8+ T cell clones, identify baseline markers of CD8+ T cell clonal sensitivity, and chart how CD8+ T cell transcriptional changes vary according to phenotypic subset and clonal size. We identified seven subsets of CD8+ T cells with divergent reactivity to ICB and found that the cytotoxic effector subset showed the greatest number of differentially expressed genes while remaining stable in clonal size after ICB. At the level of CD8+ T cell clonotypes, we found a relationship between transcriptional changes and clone size, with large clones showing a greater number of differentially regulated genes enriched for pathways including T cell receptor (TCR) signaling. Cytotoxic CD8+ effector clones were more likely to persist following ICB and were more likely to correspond with public tumor-infiltrating lymphocyte clonotypes. Last, we demonstrated that individuals whose CD8+ T cell pretreatment showed low cytotoxicity and had fewer expanded clones typically had worse outcomes after ICB treatment. This work further advances understanding of the molecular determinants of ICB response, assisting in the search for peripheral prognostic biomarkers and highlighting the importance of the baseline CD8+ immune landscape in determining ICB response in metastatic melanoma.


Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Linfocitos T CD8-positivos/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/farmacología , Ipilimumab/farmacología , Nivolumab/farmacología , Linfocitos T CD8-positivos/inmunología , Humanos , Supervivencia sin Progresión
7.
Cell Rep Med ; 2(12): 100473, 2021 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-35028614

RESUMEN

Despite its role in cancer surveillance, adoptive immunotherapy using γδ T cells has achieved limited efficacy. To enhance trafficking to bone marrow, circulating Vγ9Vδ2 T cells are expanded in serum-free medium containing TGF-ß1 and IL-2 (γδ[T2] cells) or medium containing IL-2 alone (γδ[2] cells, as the control). Unexpectedly, the yield and viability of γδ[T2] cells are also increased by TGF-ß1, when compared to γδ[2] controls. γδ[T2] cells are less differentiated and yet display increased cytolytic activity, cytokine release, and antitumor activity in several leukemic and solid tumor models. Efficacy is further enhanced by cancer cell sensitization using aminobisphosphonates or Ara-C. A number of contributory effects of TGF-ß are described, including prostaglandin E2 receptor downmodulation, TGF-ß insensitivity, and upregulated integrin activity. Biological relevance is supported by the identification of a favorable γδ[T2] signature in acute myeloid leukemia (AML). Given their enhanced therapeutic activity and compatibility with allogeneic use, γδ[T2] cells warrant evaluation in cancer immunotherapy.


Asunto(s)
Inmunoterapia Adoptiva , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/terapia , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Células de la Médula Ósea/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Medio de Cultivo Libre de Suero/farmacología , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Humanos , Inmunofenotipificación , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Activación de Linfocitos , Ratones SCID , Pronóstico
8.
Nat Med ; 26(2): 193-199, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32042196

RESUMEN

Immune checkpoint blockade (ICB) of PD-1 and CTLA-4 to treat metastatic melanoma (MM) has variable therapeutic benefit. To explore this in peripheral samples, we characterized CD8+ T cell gene expression across a cohort of patients with MM receiving anti-PD-1 alone (sICB) or in combination with anti-CTLA-4 (cICB). Whereas CD8+ transcriptional responses to sICB and cICB involve a shared gene set, the magnitude of cICB response is over fourfold greater, with preferential induction of mitosis- and interferon-related genes. Early samples from patients with durable clinical benefit demonstrated overexpression of T cell receptor-encoding genes. By mapping T cell receptor clonality, we find that responding patients have more large clones (those occupying >0.5% of repertoire) post-treatment than non-responding patients or controls, and this correlates with effector memory T cell percentage. Single-cell RNA-sequencing of eight post-treatment samples demonstrates that large clones overexpress genes implicated in cytotoxicity and characteristic of effector memory T cells, including CCL4, GNLY and NKG7. The 6-month clinical response to ICB in patients with MM is associated with the large CD8+ T cell clone count 21 d after treatment and agnostic to clonal specificity, suggesting that post-ICB peripheral CD8+ clonality can provide information regarding long-term treatment response and, potentially, facilitate treatment stratification.


Asunto(s)
Linfocitos T CD8-positivos/citología , Antígeno CTLA-4/inmunología , Inmunoterapia/métodos , Melanoma/inmunología , Melanoma/terapia , Adulto , Anticuerpos/uso terapéutico , Antígenos de Diferenciación de Linfocitos T/genética , Proliferación Celular , Quimiocina CCL4/genética , Estudios de Cohortes , Femenino , Perfilación de la Expresión Génica , Humanos , Sistema Inmunológico , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Metástasis de la Neoplasia , Receptor de Muerte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Análisis de la Célula Individual , Adulto Joven
9.
Nat Commun ; 10(1): 4575, 2019 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-31594933

RESUMEN

IL-7 is a key factor in T cell immunity and common variants at IL7R, encoding its receptor, are associated with autoimmune disease susceptibility. IL7R mRNA is induced in stimulated monocytes, yet a function for IL7R in monocyte biology remains unexplored. Here we characterize genetic regulation of IL7R at the protein level in healthy individuals, and find that monocyte surface and soluble IL7R (sIL7R) are markedly induced by lipopolysaccharide. In monocytes, both surface IL7R and sIL7R expression strongly associate with allelic carriage of rs6897932, a disease-associated IL7R polymorphism. Monocytes produce more sIL7R than CD4 + T cells, and the amount is additionally correlated with the expression of DDX39A, encoding a splicing factor. Synovial fluid-derived monocytes from patients with spondyloarthritis are enriched for IL7R+ cells with a unique transcriptional profile that overlaps with IL-7-induced gene sets. Our data thus suggest a previously unappreciated function for monocytes in IL-7 biology and IL7R-associated diseases.


Asunto(s)
Autoinmunidad/genética , Subunidad alfa del Receptor de Interleucina-7/genética , Interleucina-7/inmunología , Monocitos/inmunología , Espondilitis Anquilosante/genética , Alelos , ARN Helicasas DEAD-box/inmunología , ARN Helicasas DEAD-box/metabolismo , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Voluntarios Sanos , Humanos , Interleucina-7/metabolismo , Subunidad alfa del Receptor de Interleucina-7/inmunología , Subunidad alfa del Receptor de Interleucina-7/metabolismo , Lipopolisacáridos/inmunología , Monocitos/metabolismo , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Espondilitis Anquilosante/inmunología , Espondilitis Anquilosante/patología , Líquido Sinovial/citología , Líquido Sinovial/inmunología , Regulación hacia Arriba/inmunología
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