RESUMEN
Cell-mediated immunity is driven by antigenic peptide presentation on major histocompatibility complex (MHC) molecules. Specialized proteasome complexes called immunoproteasomes process viral, bacterial, and tumor antigens for presentation on MHC class I molecules, which can induce CD8 T cells to mount effective immune responses. Immunoproteasomes are distinguished by three subunits that alter the catalytic activity of the proteasome and are inducible by inflammatory stimuli such as interferon-γ (IFN-γ). This inducible activity places them in central roles in cancer, autoimmunity, and inflammation. While accelerated proteasomal degradation is an important tumorigenic mechanism deployed by several cancers, there is some ambiguity regarding the role of immunoproteasome induction in neoplastic transformation. Understanding the mechanistic and functional relevance of the immunoproteasome provides essential insights into developing targeted therapies, including overcoming resistance to standard proteasome inhibition and immunomodulation of the tumor microenvironment. In this review, we discuss the roles of the immunoproteasome in different cancers.
Asunto(s)
Neoplasias/inmunología , Complejo de la Endopetidasa Proteasomal/inmunología , Subunidades de Proteína/inmunología , Animales , Humanos , Modelos Biológicos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Complejo de la Endopetidasa Proteasomal/química , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , Subunidades de Proteína/químicaRESUMEN
There has been a dramatic increase in the detection of lung nodules, many of which are preneoplasia atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) or invasive adenocarcinoma (ADC). The molecular landscape and the evolutionary trajectory of lung preneoplasia have not been well defined. Here, we perform multi-region exome sequencing of 116 resected lung nodules including AAH (n = 22), AIS (n = 27), MIA (n = 54) and synchronous ADC (n = 13). Comparing AAH to AIS, MIA and ADC, we observe progressive genomic evolution at the single nucleotide level and demarcated evolution at the chromosomal level supporting the early lung carcinogenesis model from AAH to AIS, MIA and ADC. Subclonal analyses reveal a higher proportion of clonal mutations in AIS/MIA/ADC than AAH suggesting neoplastic transformation of lung preneoplasia is predominantly associated with a selective sweep of unfit subclones. Analysis of multifocal pulmonary nodules from the same patients reveal evidence of convergent evolution.
Asunto(s)
Adenocarcinoma del Pulmón/genética , Evolución Molecular , Neoplasias Pulmonares/genética , Pulmón/patología , Lesiones Precancerosas/genética , Adenocarcinoma del Pulmón/patología , Anciano , Anciano de 80 o más Años , Carcinogénesis/genética , Femenino , Humanos , Hiperplasia/genética , Hiperplasia/patología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Lesiones Precancerosas/patología , Secuenciación del ExomaRESUMEN
While there is considerable interest at the present time in the development of so-called liquid biopsy approaches for cancer detection based notably on circulating tumor DNA, there are other types of potential biomarkers that show promise for lung cancer screening and early detection. Here we review approaches and some of the promising markers based on proteomics, metabolomics and the immune response to tumor antigens in the form of autoantibodies.