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1.
Cancer Immunol Res ; 10(11): 1354-1369, 2022 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-36095236

RESUMEN

Tumor-associated macrophages (TAM) are one of the most abundant cell types in many solid tumors and typically exert protumor effects. This has led to an interest in macrophage-depleting agents for cancer therapy, but approaches developed to date have had limited success in clinical trials. Here, we report the development of a strategy for TAM depletion in mouse solid tumor models using chimeric antigen receptor (CAR) T cells targeting the macrophage marker F4/80 (F4.CAR-T). F4.CAR-T cells effectively killed macrophages in vitro and in vivo without toxicity. When injected into mice bearing orthotopic lung tumors, F4.CAR-T cells infiltrated tumor lesions and delayed tumor growth comparably with PD-1 blockade, and significantly extended mouse survival. Antitumor effects were mediated by F4.CAR-T-produced IFNγ, which promoted upregulation of MHC molecules on cancer cells and tumor-infiltrating myeloid cells. Notably, F4.CAR-T promoted expansion of endogenous CD8 T cells specific for tumor-associated antigen and led to immune editing of highly antigenic tumor cell clones. Antitumor impact was also observed in mouse models of ovarian and pancreatic cancer. These studies provide proof of principle to support CAR T-cell targeting of TAMs as a means to enhance antitumor immunity.


Asunto(s)
Receptores Quiméricos de Antígenos , Linfocitos T , Animales , Ratones , Antígenos de Neoplasias , Línea Celular Tumoral , Modelos Animales de Enfermedad , Inmunoterapia Adoptiva , Macrófagos/metabolismo , Receptores Quiméricos de Antígenos/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Progresión de la Enfermedad
2.
Life Sci Alliance ; 3(2)2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31879279

RESUMEN

CLIC4 and CLIC1 are members of the well-conserved chloride intracellular channel proteins (CLICs) structurally related to glutathione-S-transferases. Here, we report new roles of CLICs in cytokinesis. At the onset of cytokinesis, CLIC4 accumulates at the cleavage furrow and later localizes to the midbody in a RhoA-dependent manner. The cell cycle-dependent localization of CLIC4 is abolished when its glutathione S-transferase activity-related residues (C35A and F37D) are mutated. Ezrin, anillin, and ALIX are identified as interaction partners of CLIC4 at the cleavage furrow and midbody. Strikingly, CLIC4 facilitates the activation of ezrin at the cleavage furrow and reciprocally inhibition of ezrin activation diminishes the translocation of CLIC4 to the cleavage furrow. Furthermore, knockouts of CLIC4 and CLIC1 cause abnormal blebbing at the polar cortex and regression of the cleavage furrow at late cytokinesis leading to multinucleated cells. We conclude that CLIC4 and CLIC1 function together with ezrin where they bridge plasma membrane and actin cytoskeleton at the polar cortex and cleavage furrow to promote cortical stability and successful completion of cytokinesis in mammalian cells.


Asunto(s)
Actinas/metabolismo , Membrana Celular/metabolismo , Canales de Cloruro/metabolismo , Citocinesis/genética , Citoesqueleto de Actina/metabolismo , Proteínas de Unión al Calcio/metabolismo , Proteínas de Ciclo Celular/metabolismo , Canales de Cloruro/genética , Proteínas del Citoesqueleto/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Técnicas de Inactivación de Genes , Células HEK293 , Células HeLa , Humanos , Proteínas de Microfilamentos/metabolismo , Mapas de Interacción de Proteínas , Transfección , Proteína de Unión al GTP rhoA/genética , Proteína de Unión al GTP rhoA/metabolismo
3.
Immunity ; 49(4): 764-779.e9, 2018 10 16.
Artículo en Inglés | MEDLINE | ID: mdl-30332632

RESUMEN

The major types of non-small-cell lung cancer (NSCLC)-squamous cell carcinoma and adenocarcinoma-have distinct immune microenvironments. We developed a genetic model of squamous NSCLC on the basis of overexpression of the transcription factor Sox2, which specifies lung basal cell fate, and loss of the tumor suppressor Lkb1 (SL mice). SL tumors recapitulated gene-expression and immune-infiltrate features of human squamous NSCLC; such features included enrichment of tumor-associated neutrophils (TANs) and decreased expression of NKX2-1, a transcriptional regulator that specifies alveolar cell fate. In Kras-driven adenocarcinomas, mis-expression of Sox2 or loss of Nkx2-1 led to TAN recruitment. TAN recruitment involved SOX2-mediated production of the chemokine CXCL5. Deletion of Nkx2-1 in SL mice (SNL) revealed that NKX2-1 suppresses SOX2-driven squamous tumorigenesis by repressing adeno-to-squamous transdifferentiation. Depletion of TANs in SNL mice reduced squamous tumors, suggesting that TANs foster squamous cell fate. Thus, lineage-defining transcription factors determine the tumor immune microenvironment, which in turn might impact the nature of the tumor.


Asunto(s)
Diferenciación Celular/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Factores de Transcripción SOXB1/inmunología , Microambiente Tumoral/inmunología , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Diferenciación Celular/genética , Línea Celular Tumoral , Linaje de la Célula/genética , Linaje de la Célula/inmunología , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neutrófilos/inmunología , Neutrófilos/metabolismo , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismo , Factor Nuclear Tiroideo 1/genética , Factor Nuclear Tiroideo 1/metabolismo , Microambiente Tumoral/genética
5.
Cell Cycle ; 16(16): 1489-1498, 2017 Aug 18.
Artículo en Inglés | MEDLINE | ID: mdl-28737478

RESUMEN

Small cell lung cancer (SCLC) is one of the most deadly cancers and currently lacks effective targeted treatment options. Recent advances in the molecular characterization of SCLC has provided novel insight into the biology of this disease and raises hope for a paradigm shift in the treatment of SCLC. We and others have identified activation of MYC as a driver of susceptibility to Aurora kinase inhibition in SCLC cells and tumors that translates into a therapeutic option for the targeted treatment of MYC-driven SCLC. While MYC shares major features with its paralogs MYCN and MYCL, the sensitivity to Aurora kinase inhibitors is unique for MYC-driven SCLC. In this review, we will compare the distinct molecular features of the 3 MYC family members and address the potential implications for targeted therapy of SCLC.


Asunto(s)
Neoplasias Pulmonares/genética , Oncogenes , Proteínas Proto-Oncogénicas c-myc/metabolismo , Carcinoma Pulmonar de Células Pequeñas/genética , Animales , Modelos Animales de Enfermedad , Humanos , Transducción de Señal
6.
Cancer Cell ; 31(2): 270-285, 2017 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-28089889

RESUMEN

Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low "variant" subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which, combined with chemotherapy, strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a potential targeted treatment approach for MYC-driven SCLC.


Asunto(s)
Aurora Quinasas/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-myc/fisiología , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Progresión de la Enfermedad , Humanos , Neoplasias Pulmonares/etiología , Ratones , Carcinoma Pulmonar de Células Pequeñas/etiología
7.
EMBO J ; 34(2): 251-65, 2015 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-25476450

RESUMEN

The cell surface is the cellular compartment responsible for communication with the environment. The interior of mammalian cells undergoes dramatic reorganization when cells enter mitosis. These changes are triggered by activation of the CDK1 kinase and have been studied extensively. In contrast, very little is known of the cell surface changes during cell division. We undertook a quantitative proteomic comparison of cell surface-exposed proteins in human cancer cells that were tightly synchronized in mitosis or interphase. Six hundred and twenty-eight surface and surface-associated proteins in HeLa cells were identified; of these, 27 were significantly enriched at the cell surface in mitosis and 37 in interphase. Using imaging techniques, we confirmed the mitosis-selective cell surface localization of protocadherin PCDH7, a member of a family with anti-adhesive roles in embryos. We show that PCDH7 is required for development of full mitotic rounding pressure at the onset of mitosis. Our analysis provided basic information on how cell cycle progression affects the cell surface. It also provides potential pharmacodynamic biomarkers for anti-mitotic cancer chemotherapy.


Asunto(s)
Biomarcadores/metabolismo , Interfase/fisiología , Proteínas de la Membrana/metabolismo , Mitosis/fisiología , Proteoma/análisis , Proteómica/métodos , Biotinilación , Cadherinas/metabolismo , Cromatografía de Afinidad , Células HeLa , Humanos , Células MCF-7 , Protocadherinas , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
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