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1.
Cancer Sci ; 115(8): 2540-2552, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38845192

RESUMEN

The prognosis of patients with peripheral T-cell lymphoma (PTCL) depends on bone marrow involvement (BMI). The bone marrow (BM) tumor microenvironment in PTCL remains unclear. We performed single-cell RNA sequencing (scRNA-seq) on 11 fresh BM samples from patients with BMI to reveal the associations of immune landscape and genetic variations with the prognosis of PTCL patients. Compared with PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL) had a higher number of T cells, lower number of lymphocytes, and greater inflammation. Immune heterogeneity in AITL is associated with prognosis. In particular, specific T-cell receptor (TCR) T cells are enriched in patients with good response to anti-CD30 therapy. We observed RhoA mutation-associated neoantigens. Chidamide-treated patients had a higher number of CD4+ regulatory cells and a better treatment response compared with other patients. In the nonresponder group, T-cell enrichment progressed to secondary B-cell enrichment and subsequently diffuse large B-cell lymphoma. Moreover, AITL patients with lymphoma-associated hemophagocytic syndrome had more T follicular helper (Tfh) cells with copy number variations in CHR5. To our knowledge, this study is the first to reveal the single-cell landscape of BM microenvironment heterogeneity in PTCL patients with BMI. scRNA-seq can be used to investigate the immune heterogeneity and genetic variations in AITL associated with prognosis.


Asunto(s)
Médula Ósea , Linfoma de Células T Periférico , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Linfoma de Células T Periférico/inmunología , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/patología , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Médula Ósea/patología , Médula Ósea/inmunología , Masculino , Femenino , Pronóstico , Persona de Mediana Edad , Anciano , Mutación , Receptores de Antígenos de Linfocitos T/genética , Proteína de Unión al GTP rhoA/genética , Adulto , Heterogeneidad Genética
2.
Front Immunol ; 12: 728082, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34512660

RESUMEN

CD8+ T cells are major components of adaptive immunity and confer robust protective cellular immunity, which requires adequate T-cell numbers, targeted migration, and efficient T-cell proliferation. Altered CD8+ T-cell homeostasis and impaired proliferation result in dysfunctional immune response to infection or tumorigenesis. However, intrinsic factors controlling CD8+ T-cell homeostasis and immunity remain largely elusive. Here, we demonstrate the prominent role of Brd4 on CD8+ T cell homeostasis and immune response. By upregulating Myc and GLUT1 expression, Brd4 facilitates glucose uptake and energy production in mitochondria, subsequently supporting naïve CD8+ T-cell survival. Besides, Brd4 promotes the trafficking of naïve CD8+ T cells partially through maintaining the expression of homing receptors (CD62L and LFA-1). Furthermore, Brd4 is required for CD8+ T cell response to antigen stimulation, as Brd4 deficiency leads to a severe defect in clonal expansion and terminal differentiation by decreasing glycolysis. Importantly, as JQ1, a pan-BRD inhibitor, severely dampens CD8+ T-cell immune response, its usage as an anti-tumor agent or latency-reversing agent for human immunodeficiency virus type I (HIV-1) should be more cautious. Collectively, our study identifies a previously-unexpected role of Brd4 in the metabolic regulation of CD8+ T cell-mediated immune surveillance and also provides a potential immunomodulation target.


Asunto(s)
Antígenos Virales/inmunología , Linfocitos T CD8-positivos/virología , Proliferación Celular , Activación de Linfocitos , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/inmunología , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Traslado Adoptivo , Animales , Azepinas/farmacología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/trasplante , Proliferación Celular/efectos de los fármacos , Chlorocebus aethiops , Modelos Animales de Enfermedad , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/metabolismo , Glucólisis , Interacciones Huésped-Patógeno , Activación de Linfocitos/efectos de los fármacos , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/metabolismo , Virus de la Coriomeningitis Linfocítica/patogenicidad , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/genética , Mitocondrias/inmunología , Mitocondrias/metabolismo , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Triazoles/farmacología , Células Vero
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