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1.
Immunity ; 56(7): 1631-1648.e10, 2023 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-37392737

RESUMO

CD137 (4-1BB)-activating receptor represents a promising cancer immunotherapeutic target. Yet, the cellular program driven by CD137 and its role in cancer immune surveillance remain unresolved. Using T cell-specific deletion and agonist antibodies, we found that CD137 modulates tumor infiltration of CD8+-exhausted T (Tex) cells expressing PD1, Lag-3, and Tim-3 inhibitory receptors. T cell-intrinsic, TCR-independent CD137 signaling stimulated the proliferation and the terminal differentiation of Tex precursor cells through a mechanism involving the RelA and cRel canonical NF-κB subunits and Tox-dependent chromatin remodeling. While Tex cell accumulation induced by prophylactic CD137 agonists favored tumor growth, anti-PD1 efficacy was improved with subsequent CD137 stimulation in pre-clinical mouse models. Better understanding of T cell exhaustion has crucial implications for the treatment of cancer and infectious diseases. Our results identify CD137 as a critical regulator of Tex cell expansion and differentiation that holds potential for broad therapeutic applications.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Camundongos , Animais , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral , Diferenciação Celular , Proliferação de Células , Receptores de Antígenos de Linfócitos T
2.
Blood ; 144(12): 1271-1283, 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-38875515

RESUMO

ABSTRACT: The promising results obtained with immunotherapeutic approaches for multiple myeloma (MM) call for a better stratification of patients based on immune components. The most pressing being cytotoxic lymphocytes such as natural killer (NK) cells that are mandatory for MM surveillance and therapy. Here, we performed a single-cell RNA sequencing analysis of NK cells from 10 patients with MM and 10 age/sex-matched healthy donors that revealed important transcriptomic changes in the NK cell landscape affecting both the bone marrow (BM) and peripheral blood compartment. The frequency of mature cytotoxic CD56dim NK cell subsets was reduced in patients with MM at the advantage of late-stage NK cell subsets expressing NF-κB and interferon-I inflammatory signatures. These NK cell subsets accumulating in patients with MM were characterized by low CD16 and CD226 expression and poor cytotoxic functions. MM CD16/CD226Lo NK cells also had adhesion defects with reduced lymphocyte function-associated antigen 1 (LFA-1) integrin activation and actin polymerization that may account for their limited effector functions in vitro. Finally, analysis of BM-infiltrating NK cells in a retrospective cohort of 177 patients with MM from the Intergroupe Francophone du Myélome (IFM) 2009 trial demonstrated that a high frequency of NK cells and their low CD16 and CD226 expression were associated with a shorter overall survival. Thus, CD16/CD226Lo NK cells with reduced effector functions accumulate along MM development and negatively affect patients' clinical outcomes. Given the growing interest in harnessing NK cells to treat myeloma, this improved knowledge around MM-associated NK cell dysfunction will stimulate the development of more efficient immunotherapeutic drugs against MM.


Assuntos
Adesão Celular , Células Matadoras Naturais , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Prognóstico , Feminino , Masculino , Citotoxicidade Imunológica , Antígenos de Diferenciação de Linfócitos T/metabolismo , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Antígeno-1 Associado à Função Linfocitária/metabolismo , Receptores de IgG , Proteínas Ligadas por GPI
3.
Biofactors ; 46(4): 653-664, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32384218

RESUMO

Formation of atherosclerotic plaques, called atherogenesis, is a complex process affected by genetic and environmental factors. It was proposed that endoplasmic reticulum (ER) stress is an important factor in the pathogenesis of atherosclerosis and that vitamin E affects atherosclerotic plaque formation via its antioxidant properties. Here, we investigated ER stress-related molecular mechanisms in high-cholesterol diet (HCD, 2%)-induced atherosclerosis model and the role of vitamin E supplementation in it, beyond its antioxidant properties. The consequences of HCD and vitamin E supplementation were examined by determining protein levels of ER stress markers in aortic tissues. As vitamin E supplementation acts on several unfolded protein response (UPR) factors, it decreased ER stress induced by HCD. To elucidate the associated pathways, gene expression profiling was performed, revealing differentially expressed genes enriched in ER stress-related pathways such as the proteasome and the apoptosis pathways. We further assessed the proteasomal activity impaired by HCD in the aorta and showed that vitamin E reversed it to that of control animals. Overall, the study characterized the effects of HCD and vitamin E on ER stress-related gene expression, revealing the role of proteolytic systems during atherogenesis.


Assuntos
Antioxidantes/farmacologia , Aterosclerose/genética , Colesterol/administração & dosagem , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hipercolesterolemia/genética , Placa Aterosclerótica/genética , Vitamina E/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Aterosclerose/etiologia , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Dieta Hiperlipídica/efeitos adversos , Estresse do Retículo Endoplasmático/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes/efeitos dos fármacos , Hipercolesterolemia/etiologia , Hipercolesterolemia/patologia , Hipercolesterolemia/prevenção & controle , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Masculino , Anotação de Sequência Molecular , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/patologia , Placa Aterosclerótica/prevenção & controle , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Coelhos , Resposta a Proteínas não Dobradas/efeitos dos fármacos
4.
Clin Breast Cancer ; 20(4): 332-343.e3, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32201164

RESUMO

BACKGROUND: Cells detaching from the primary tumor site are metastasis initiator cells, and the detection of CTC, known as liquid biopsy, is an important test of biomarkers of cancer progression. We investigated the molecular characterization of circulating tumor cells (CTCs), profiled the plasma microRNA (miR) content, and analyzed the relationship with the clinical outcomes by sampling the peripheral blood from patients with locally advanced breast cancer before and after neoadjuvant chemotherapy. PATIENTS AND METHODS: Markers of breast cancer, epithelial-mesenchymal transition (EMT), drug resistance, and stem cells were used for CTC isolation and characterization. Plasma miR profiles were obtained from selected patients with CTC positivity determined using next-generation sequencing. RESULTS: The proportion of CTC, EMT, and stem cell marker positivity was 16.7%, 8.3%, and 25% before and 18.2%, 15.2%, and 9.1% after treatment, respectively. A significant correlation was found between the pretreatment CTCs and ALDH1 positivity (P = .0245). These CTCs with stemness properties were observed in most hormone receptor-positive, human epidermal growth factor receptor 2-negative cases and were also present with a high incidence in cases of early metastasis. miR-146b-5p and miR-199a-5p, which are involved in metastasis, invasion, and EMT, were accompanied by CTC positivity, and miR-4646-3p was associated with the development of early metastasis. CONCLUSIONS: Molecular characterization of CTCs and miR profiling of serial samples from patients with locally advanced breast cancer during neoadjuvant chemotherapy appears to be a very useful in predicting cure and clinical course and might be a key to developing new targeted therapies.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/terapia , MicroRNAs/sangue , Terapia Neoadjuvante , Células Neoplásicas Circulantes/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/sangue , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Estudos de Viabilidade , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Resultado do Tratamento
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