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1.
Science ; 383(6685): eadi3808, 2024 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-38386728

RESUMEN

Cancer risk is influenced by inherited mutations, DNA replication errors, and environmental factors. However, the influence of genetic variation in immunosurveillance on cancer risk is not well understood. Leveraging population-level data from the UK Biobank and FinnGen, we show that heterozygosity at the human leukocyte antigen (HLA)-II loci is associated with reduced lung cancer risk in smokers. Fine-mapping implicated amino acid heterozygosity in the HLA-II peptide binding groove in reduced lung cancer risk, and single-cell analyses showed that smoking drives enrichment of proinflammatory lung macrophages and HLA-II+ epithelial cells. In lung cancer, widespread loss of HLA-II heterozygosity (LOH) favored loss of alleles with larger neopeptide repertoires. Thus, our findings nominate genetic variation in immunosurveillance as a critical risk factor for lung cancer.


Asunto(s)
Predisposición Genética a la Enfermedad , Antígenos de Histocompatibilidad Clase II , Vigilancia Inmunológica , Pérdida de Heterocigocidad , Neoplasias Pulmonares , Humanos , Antígenos de Histocompatibilidad Clase II/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Macrófagos Alveolares/inmunología , Factores de Riesgo , Fumar/inmunología , Vigilancia Inmunológica/genética , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Mapeo Cromosómico , Polimorfismo de Nucleótido Simple
3.
Nat Rev Immunol ; 22(6): 336, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35484323

Asunto(s)
Macrófagos , Páncreas , Humanos
4.
Cell Rep ; 37(7): 110005, 2021 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-34788626

RESUMEN

Young adult cancer has increased in incidence worldwide, but its molecular etiologies remain unclear. We systematically characterize genomic profiles of young adult tumors with ages of onset ≤50 years and compare them to later-onset tumors using over 6,000 cases across 14 cancer types. While young adult tumors generally show lower mutation burdens and comparable copy-number variation rates compared to later-onset cases, they are enriched for multiple driver mutations and copy-number alterations in subtype-specific contexts. Characterization of tumor immune microenvironments reveals pan-cancer patterns of elevated TGF-ß response/dendritic cells and lower IFN-γ response/macrophages relative to later-onset tumors, corresponding to age-related responses to immunotherapy in several cancer types. Finally, we identify prevalent clinically actionable events that disproportionally affect young adult or later-onset cases. The resulting catalog of age-related molecular drivers can guide precision diagnostics and treatments for young adult cancer.


Asunto(s)
Factores de Edad , Neoplasias/diagnóstico , Neoplasias/genética , Adulto , Anciano , Variaciones en el Número de Copia de ADN/genética , Metilación de ADN , Bases de Datos Genéticas , Epigénesis Genética/genética , Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/genética , Genómica/métodos , Humanos , Inmunoterapia/métodos , Persona de Mediana Edad , Mutación/genética , Neoplasias/fisiopatología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Adulto Joven
5.
Nat Rev Immunol ; 21(3): 135, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33568784
6.
Nat Commun ; 12(1): 755, 2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33531483

RESUMEN

Fecal microbiota transplantation (FMT) is a successful therapeutic strategy for treating recurrent Clostridioides difficile infection. Despite remarkable efficacy, implementation of FMT therapy is limited and the mechanism of action remains poorly understood. Here, we demonstrate a critical role for the immune system in supporting FMT using a murine C. difficile infection system. Following FMT, Rag1 heterozygote mice resolve C. difficile while littermate Rag1-/- mice fail to clear the infection. Targeted ablation of adaptive immune cell subsets reveal a necessary role for CD4+ Foxp3+ T-regulatory cells, but not B cells or CD8+ T cells, in FMT-mediated resolution of C. difficile infection. FMT non-responsive mice exhibit exacerbated inflammation, impaired engraftment of the FMT bacterial community and failed restoration of commensal bacteria-derived secondary bile acid metabolites in the large intestine. These data demonstrate that the host's inflammatory immune status can limit the efficacy of microbiota-based therapeutics to treat C. difficile infection.


Asunto(s)
Clostridioides difficile/patogenicidad , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Infecciones por Clostridium/inmunología , Infecciones por Clostridium/metabolismo , Heces/microbiología , Factores de Transcripción Forkhead/metabolismo , Proteínas de Homeodominio/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Ratones , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo
7.
Nat Rev Immunol ; 20(9): 521, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32737461
8.
Immunity ; 52(6): 910-941, 2020 06 16.
Artículo en Inglés | MEDLINE | ID: mdl-32505227

RESUMEN

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this Review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection.


Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/inmunología , Neumonía Viral/inmunología , Animales , COVID-19 , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/terapia , Susceptibilidad a Enfermedades , Humanos , Inmunidad Innata , Memoria Inmunológica , Inflamación/inmunología , Inflamación/virología , Linfocitos/inmunología , Células Mieloides/inmunología , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/patología , Neumonía Viral/terapia , SARS-CoV-2
9.
Nat Rev Immunol ; 20(6): 352, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32346092
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