Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
1.
Nat Immunol ; 24(11): 1908-1920, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37828379

RESUMO

Co-inhibitory and checkpoint molecules suppress T cell function in the tumor microenvironment, thereby rendering T cells dysfunctional. Although immune checkpoint blockade is a successful treatment option for multiple human cancers, severe autoimmune-like adverse effects can limit its application. Here, we show that the gene encoding peptidoglycan recognition protein 1 (PGLYRP1) is highly coexpressed with genes encoding co-inhibitory molecules, indicating that it might be a promising target for cancer immunotherapy. Genetic deletion of Pglyrp1 in mice led to decreased tumor growth and an increased activation/effector phenotype in CD8+ T cells, suggesting an inhibitory function of PGLYRP1 in CD8+ T cells. Surprisingly, genetic deletion of Pglyrp1 protected against the development of experimental autoimmune encephalomyelitis, a model of autoimmune disease in the central nervous system. PGLYRP1-deficient myeloid cells had a defect in antigen presentation and T cell activation, indicating that PGLYRP1 might function as a proinflammatory molecule in myeloid cells during autoimmunity. These results highlight PGLYRP1 as a promising target for immunotherapy that, when targeted, elicits a potent antitumor immune response while protecting against some forms of tissue inflammation and autoimmunity.


Assuntos
Encefalomielite Autoimune Experimental , Neoplasias , Animais , Humanos , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/genética , Imunoterapia , Inflamação , Doenças Neuroinflamatórias , Microambiente Tumoral
2.
Nat Immunol ; 22(12): 1577-1589, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34811546

RESUMO

Single-cell genomics technology has transformed our understanding of complex cellular systems. However, excessive cost and a lack of strategies for the purification of newly identified cell types impede their functional characterization and large-scale profiling. Here, we have generated high-content single-cell proteo-genomic reference maps of human blood and bone marrow that quantitatively link the expression of up to 197 surface markers to cellular identities and biological processes across all main hematopoietic cell types in healthy aging and leukemia. These reference maps enable the automatic design of cost-effective high-throughput cytometry schemes that outperform state-of-the-art approaches, accurately reflect complex topologies of cellular systems and permit the purification of precisely defined cell states. The systematic integration of cytometry and proteo-genomic data enables the functional capacities of precisely mapped cell states to be measured at the single-cell level. Our study serves as an accessible resource and paves the way for a data-driven era in cytometry.


Assuntos
Células Sanguíneas/metabolismo , Células da Medula Óssea/metabolismo , Separação Celular , Citometria de Fluxo , Perfilação da Expressão Gênica , Proteoma , Proteômica , Análise de Célula Única , Transcriptoma , Fatores Etários , Células Sanguíneas/imunologia , Células Sanguíneas/patologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Células Cultivadas , Bases de Dados Genéticas , Envelhecimento Saudável/genética , Envelhecimento Saudável/imunologia , Envelhecimento Saudável/metabolismo , Humanos , Leucemia/genética , Leucemia/imunologia , Leucemia/metabolismo , Leucemia/patologia , RNA-Seq , Biologia de Sistemas
3.
Cell ; 169(5): 807-823.e19, 2017 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-28479188

RESUMO

Dormant hematopoietic stem cells (dHSCs) are atop the hematopoietic hierarchy. The molecular identity of dHSCs and the mechanisms regulating their maintenance or exit from dormancy remain uncertain. Here, we use single-cell RNA sequencing (RNA-seq) analysis to show that the transition from dormancy toward cell-cycle entry is a continuous developmental path associated with upregulation of biosynthetic processes rather than a stepwise progression. In addition, low Myc levels and high expression of a retinoic acid program are characteristic for dHSCs. To follow the behavior of dHSCs in situ, a Gprc5c-controlled reporter mouse was established. Treatment with all-trans retinoic acid antagonizes stress-induced activation of dHSCs by restricting protein translation and levels of reactive oxygen species (ROS) and Myc. Mice maintained on a vitamin A-free diet lose HSCs and show a disrupted re-entry into dormancy after exposure to inflammatory stress stimuli. Our results highlight the impact of dietary vitamin A on the regulation of cell-cycle-mediated stem cell plasticity. VIDEO ABSTRACT.


Assuntos
Células-Tronco Hematopoéticas/citologia , Transdução de Sinais , Tretinoína/farmacologia , Vitamina A/administração & dosagem , Animais , Vias Biossintéticas , Técnicas de Cultura de Células , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular , Dieta , Perfilação da Expressão Gênica , Células-Tronco Hematopoéticas/efeitos dos fármacos , Camundongos , Poli I-C/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Análise de Célula Única , Estresse Fisiológico , Vitamina A/farmacologia , Vitaminas/administração & dosagem , Vitaminas/farmacologia
4.
Dev Cell ; 58(24): 2914-2929.e7, 2023 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-38113852

RESUMO

Low-grade chronic inflammation is a hallmark of ageing, associated with impaired tissue function and disease development. However, how cell-intrinsic and -extrinsic factors collectively establish this phenotype, termed inflammaging, remains poorly understood. We addressed this question in the mouse intestinal epithelium, using mouse organoid cultures to dissect stem cell-intrinsic and -extrinsic sources of inflammaging. At the single-cell level, we found that inflammaging is established differently along the crypt-villus axis, with aged intestinal stem cells (ISCs) strongly upregulating major histocompatibility complex class II (MHC-II) genes. Importantly, the inflammaging phenotype was stably propagated by aged ISCs in organoid cultures and associated with increased chromatin accessibility at inflammation-associated loci in vivo and ex vivo, indicating cell-intrinsic inflammatory memory. Mechanistically, we show that the expression of inflammatory genes is dependent on STAT1 signaling. Together, our data identify that intestinal inflammaging in mice is promoted by a cell-intrinsic mechanism, stably propagated by ISCs, and associated with a disbalance in immune homeostasis.


Assuntos
Mucosa Intestinal , Intestinos , Camundongos , Animais , Células-Tronco , Fenótipo , Inflamação
5.
Nat Commun ; 14(1): 5011, 2023 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-37591845

RESUMO

In multiple myeloma spatial differences in the subclonal architecture, molecular signatures and composition of the microenvironment remain poorly characterized. To address this shortcoming, we perform multi-region sequencing on paired random bone marrow and focal lesion samples from 17 newly diagnosed patients. Using single-cell RNA- and ATAC-seq we find a median of 6 tumor subclones per patient and unique subclones in focal lesions. Genetically identical subclones display different levels of spatial transcriptional plasticity, including nearly identical profiles and pronounced heterogeneity at different sites, which can include differential expression of immunotherapy targets, such as CD20 and CD38. Macrophages are significantly depleted in the microenvironment of focal lesions. We observe proportional changes in the T-cell repertoire but no site-specific expansion of T-cell clones in intramedullary lesions. In conclusion, our results demonstrate the relevance of considering spatial heterogeneity in multiple myeloma with potential implications for models of cell-cell interactions and disease progression.


Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/genética , Comunicação Celular , Sequenciamento de Cromatina por Imunoprecipitação , Células Clonais , Progressão da Doença , Microambiente Tumoral/genética
6.
J Hematol Oncol ; 16(1): 79, 2023 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-37481608

RESUMO

BACKGROUND: Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL). METHODS: Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 106 and 50 × 106 CARTs/m2. Leukapheresis, manufacturing and administration of CARTs were performed in-house. RESULTS: For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response. CONCLUSION: In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www. CLINICALTRIALS: gov as NCT03676504.


Assuntos
Síndromes Neurotóxicas , Humanos , Adulto , Leucaférese , Proteínas Adaptadoras de Transdução de Sinal , Antígenos CD19/uso terapêutico
7.
J Clin Invest ; 132(9)2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35499080

RESUMO

Activated SUMOylation is a hallmark of cancer. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionarily conserved function of activated SUMOylation, which attenuated the immunogenicity of tumor cells. Activated SUMOylation allowed cancer cells to evade CD8+ T cell-mediated immunosurveillance by suppressing the MHC class I (MHC-I) antigen-processing and presentation machinery (APM). Loss of the MHC-I APM is a frequent cause of resistance to cancer immunotherapies, and the pharmacological inhibition of SUMOylation (SUMOi) resulted in reduced activity of the transcriptional repressor scaffold attachment factor B (SAFB) and induction of the MHC-I APM. Consequently, SUMOi enhanced the presentation of antigens and the susceptibility of tumor cells to CD8+ T cell-mediated killing. Importantly, SUMOi also triggered the activation of CD8+ T cells and thereby drove a feed-forward loop amplifying the specific antitumor immune response. In summary, we showed that activated SUMOylation allowed tumor cells to evade antitumor immunosurveillance, and we have expanded the understanding of SUMOi as a rational therapeutic strategy for enhancing the efficacy of cancer immunotherapies.


Assuntos
Apresentação de Antígeno , Neoplasias , Antígenos de Histocompatibilidade Classe I , Humanos , Evasão da Resposta Imune , Neoplasias/patologia , Sumoilação
8.
Cell Stem Cell ; 29(5): 760-775.e10, 2022 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-35523139

RESUMO

Hematopoietic stem and progenitor cells (HSPCs) are responsible for the production of blood and immune cells. Throughout life, HSPCs acquire oncogenic aberrations that can cause hematological cancers. Although molecular programs maintaining stem cell integrity have been identified, safety mechanisms eliminating malignant HSPCs from the stem cell pool remain poorly characterized. Here, we show that HSPCs constitutively present antigens via major histocompatibility complex class II. The presentation of immunogenic antigens, as occurring during malignant transformation, triggers bidirectional interactions between HSPCs and antigen-specific CD4+ T cells, causing stem cell proliferation, differentiation, and specific exhaustion of aberrant HSPCs. This immunosurveillance mechanism effectively eliminates transformed HSPCs from the hematopoietic system, thereby preventing leukemia onset. Together, our data reveal a bidirectional interaction between HSPCs and CD4+ T cells, demonstrating that HSPCs are not only passive receivers of immunological signals but also actively engage in adaptive immune responses to safeguard the integrity of the stem cell pool.


Assuntos
Apresentação de Antígeno , Células-Tronco Hematopoéticas , Diferenciação Celular , Linfócitos T
9.
Nat Commun ; 11(1): 5414, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33110075

RESUMO

The neoplastic stromal cells of giant cell tumor of bone (GCTB) carry a mutation in H3F3A, leading to a mutant histone variant, H3.3-G34W, as a sole recurrent genetic alteration. We show that in patient-derived stromal cells H3.3-G34W is incorporated into the chromatin and associates with massive epigenetic alterations on the DNA methylation, chromatin accessibility and histone modification level, that can be partially recapitulated in an orthogonal cell line system by the introduction of H3.3-G34W. These epigenetic alterations affect mainly heterochromatic and bivalent regions and provide possible explanations for the genomic instability, as well as the osteolytic phenotype of GCTB. The mutation occurs in differentiating mesenchymal stem cells and associates with an impaired osteogenic differentiation. We propose that the observed epigenetic alterations reflect distinct differentiation stages of H3.3 WT and H3.3 MUT stromal cells and add to H3.3-G34W-associated changes.


Assuntos
Neoplasias Ósseas/genética , Tumor de Células Gigantes do Osso/genética , Histonas/genética , Osteogênese , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/fisiopatologia , Metilação de DNA , Epigênese Genética , Epigenômica , Tumor de Células Gigantes do Osso/metabolismo , Tumor de Células Gigantes do Osso/fisiopatologia , Histonas/metabolismo , Humanos , Mutação de Sentido Incorreto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA