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1.
Immunity ; 57(3): 541-558.e7, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38442708

RESUMEN

Cancer patients often receive a combination of antibodies targeting programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen-4 (CTLA4). We conducted a window-of-opportunity study in head and neck squamous cell carcinoma (HNSCC) to examine the contribution of anti-CTLA4 to anti-PD-L1 therapy. Single-cell profiling of on- versus pre-treatment biopsies identified T cell expansion as an early response marker. In tumors, anti-PD-L1 triggered the expansion of mostly CD8+ T cells, whereas combination therapy expanded both CD4+ and CD8+ T cells. Such CD4+ T cells exhibited an activated T helper 1 (Th1) phenotype. CD4+ and CD8+ T cells co-localized with and were surrounded by dendritic cells expressing T cell homing factors or antibody-producing plasma cells. T cell receptor tracing suggests that anti-CTLA4, but not anti-PD-L1, triggers the trafficking of CD4+ naive/central-memory T cells from tumor-draining lymph nodes (tdLNs), via blood, to the tumor wherein T cells acquire a Th1 phenotype. Thus, CD4+ T cell activation and recruitment from tdLNs are hallmarks of early response to anti-PD-L1 plus anti-CTLA4 in HNSCC.


Asunto(s)
Linfocitos T CD8-positivos , Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello , Antígeno B7-H1/genética , Antígeno CTLA-4 , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Linfocitos T CD4-Positivos , Microambiente Tumoral
2.
Nature ; 620(7973): 402-408, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37532929

RESUMEN

Epithelial-to-mesenchymal transition (EMT) regulates tumour initiation, progression, metastasis and resistance to anti-cancer therapy1-7. Although great progress has been made in understanding the role of EMT and its regulatory mechanisms in cancer, no therapeutic strategy to pharmacologically target EMT has been identified. Here we found that netrin-1 is upregulated in a primary mouse model of skin squamous cell carcinoma (SCC) exhibiting spontaneous EMT. Pharmacological inhibition of netrin-1 by administration of NP137, a netrin-1-blocking monoclonal antibody currently used in clinical trials in human cancer (ClinicalTrials.gov identifier NCT02977195 ), decreased the proportion of EMT tumour cells in skin SCC, decreased the number of metastases and increased the sensitivity of tumour cells to chemotherapy. Single-cell RNA sequencing revealed the presence of different EMT states, including epithelial, early and late hybrid EMT, and full EMT states, in control SCC. By contrast, administration of NP137 prevented the progression of cancer cells towards a late EMT state and sustained tumour epithelial states. Short hairpin RNA knockdown of netrin-1 and its receptor UNC5B in EPCAM+ tumour cells inhibited EMT in vitro in the absence of stromal cells and regulated a common gene signature that promotes tumour epithelial state and restricts EMT. To assess the relevance of these findings to human cancers, we treated mice transplanted with the A549 human cancer cell line-which undergoes EMT following TGFß1 administration8,9-with NP137. Netrin-1 inhibition decreased EMT in these transplanted A549 cells. Together, our results identify a pharmacological strategy for targeting EMT in cancer, opening up novel therapeutic interventions for anti-cancer therapy.


Asunto(s)
Anticuerpos Monoclonales , Carcinoma de Células Escamosas , Transición Epitelial-Mesenquimal , Netrina-1 , Neoplasias Cutáneas , Animales , Humanos , Ratones , Células A549 , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/efectos de los fármacos , Receptores de Netrina/antagonistas & inhibidores , Receptores de Netrina/deficiencia , Receptores de Netrina/genética , Netrina-1/antagonistas & inhibidores , Netrina-1/deficiencia , Netrina-1/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacología , Modelos Animales de Enfermedad , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Metástasis de la Neoplasia/tratamiento farmacológico , Análisis de Expresión Génica de una Sola Célula , RNA-Seq , Molécula de Adhesión Celular Epitelial/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Factor de Crecimiento Transformador beta1/farmacología
3.
Prog Neurobiol ; 223: 102386, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36481386

RESUMEN

Multiple lines of evidence have linked oxidative stress, tau pathology and neuronal cell cycle re-activation to Alzheimer's disease (AD). While a prevailing idea is that oxidative stress-induced neuronal cell cycle reactivation acts as an upstream trigger for pathological tau phosphorylation, others have identified tau as an inducer of cell cycle abnormalities in both mitotic and postmitotic conditions. In addition, nuclear hypophosphorylated tau has been identified as a key player in the DNA damage response to oxidative stress. Whether and to what extent these observations are causally linked remains unclear. Using immunofluorescence, fluorescence-activated nucleus sorting and single-nucleus sequencing, we report an oxidative stress-associated accumulation of nuclear hypophosphorylated tau in a subpopulation of cycling neurons confined in S phase in AD brains, near amyloid plaques. Tau downregulation in murine neurons revealed an essential role for tau to promote cell cycle progression to S phase and prevent apoptosis in response to oxidative stress. Our results suggest that tau holds oxidative stress-associated cycling neurons in S phase to escape cell death. Together, this study proposes a tau-dependent protective effect of neuronal cell cycle reactivation in AD brains and challenges the current view that the neuronal cell cycle is an early mediator of tau pathology.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Ratones , Animales , Enfermedad de Alzheimer/metabolismo , Proteínas tau/metabolismo , Fase S , Fosforilación , Estrés Oxidativo , Neuronas/metabolismo , Péptidos beta-Amiloides/metabolismo
4.
Nat Commun ; 12(1): 1119, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33602930

RESUMEN

Regulatory CD4+ T cells (Treg) prevent tumor clearance by conventional T cells (Tconv) comprising a major obstacle of cancer immune-surveillance. Hitherto, the mechanisms of Treg repertoire formation in human cancers remain largely unclear. Here, we analyze Treg clonal origin in breast cancer patients using T-Cell Receptor and single-cell transcriptome sequencing. While Treg in peripheral blood and breast tumors are clonally distinct, Tconv clones, including tumor-antigen reactive effectors (Teff), are detected in both compartments. Tumor-infiltrating CD4+ cells accumulate into distinct transcriptome clusters, including early activated Tconv, uncommitted Teff, Th1 Teff, suppressive Treg and pro-tumorigenic Treg. Trajectory analysis suggests early activated Tconv differentiation either into Th1 Teff or into suppressive and pro-tumorigenic Treg. Importantly, Tconv, activated Tconv and Treg share highly-expanded clones contributing up to 65% of intratumoral Treg. Here we show that Treg in human breast cancer may considerably stem from antigen-experienced Tconv converting into secondary induced Treg through intratumoral activation.


Asunto(s)
Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Linfocitos T Reguladores/inmunología , Antígenos de Neoplasias/metabolismo , Neoplasias de la Mama/sangre , Neoplasias de la Mama/genética , Línea Celular Tumoral , Proliferación Celular , Células Clonales , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Activación de Linfocitos/inmunología , Estadificación de Neoplasias , Receptores de Antígenos de Linfocitos T/inmunología , Análisis de la Célula Individual , Células TH1/inmunología , Transcriptoma/genética
5.
Cell Rep ; 31(5): 107597, 2020 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-32375047

RESUMEN

Fibrosis and fat replacement in skeletal muscle are major complications that lead to a loss of mobility in chronic muscle disorders, such as muscular dystrophy. However, the in vivo properties of adipogenic stem and precursor cells remain unclear, mainly due to the high cell heterogeneity in skeletal muscles. Here, we use single-cell RNA sequencing to decomplexify interstitial cell populations in healthy and dystrophic skeletal muscles. We identify an interstitial CD142-positive cell population in mice and humans that is responsible for the inhibition of adipogenesis through GDF10 secretion. Furthermore, we show that the interstitial cell composition is completely altered in muscular dystrophy, with a near absence of CD142-positive cells. The identification of these adipo-regulatory cells in the skeletal muscle aids our understanding of the aberrant fat deposition in muscular dystrophy, paving the way for treatments that could counteract degeneration in patients with muscular dystrophy.


Asunto(s)
Adipogénesis/fisiología , Diferenciación Celular/fisiología , Células Intersticiales del Testículo/citología , Músculo Esquelético/patología , Distrofia Muscular de Duchenne/patología , Animales , Fibrosis/metabolismo , Fibrosis/patología , Humanos , Masculino , Ratones , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/metabolismo
6.
Dev Cell ; 51(2): 236-254.e12, 2019 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-31543445

RESUMEN

Bone repair and regeneration critically depend on the activation and recruitment of osteogenesis-competent skeletal stem and progenitor cells (SSPCs). Yet, the origin and triggering cues for SSPC propagation and migration remain largely elusive. Through bulk and single-cell transcriptome profiling of fetal osterix (Osx)-expressing cells, followed by lineage mapping, cell tracing, and conditional mouse mutagenesis, we here identified PDGF-PDGFRß signaling as critical functional mediator of SSPC expansion, migration, and angiotropism during bone repair. Our data show that cells marked by a history of Osx expression, including those arising in fetal or early postnatal periods, represent or include SSPCs capable of delivering all the necessary differentiated progeny to repair acute skeletal injuries later in life, provided that they express functional PDGFRß. Mechanistically, MMP-9 and VCAM-1 appear to be involved downstream of PDGF-PDGFRß. Our results reveal considerable cellular dynamism in the skeletal system and show that activation and recruitment of SSPCs for bone repair require functional PDGFRß signaling.


Asunto(s)
Regeneración Ósea/fisiología , Diferenciación Celular/fisiología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Células Madre/metabolismo , Animales , Ratones , Osteogénesis/fisiología , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de Señal/fisiología
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