RESUMO
Differentiation of proinflammatory CD4+ conventional T cells (Tconv) is critical for productive antitumor responses yet their elicitation remains poorly understood. We comprehensively characterized myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4+ Tconv, but then fail to support antitumor CD4+ Tconv differentiation. Regulatory T cell (Treg) depletion enhanced their capacity to elicit strong CD4+ Tconv responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice, their abundance relative to Treg predicts protective ICOS+ PD-1lo CD4+ Tconv phenotypes and survival. Further, in melanoma patients with low Treg abundance, intratumoral cDC2 density alone correlates with abundant CD4+ Tconv and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway that restrains cDC2 and whose reversal enhances CD4+ Tconv abundance and controls tumor growth.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Animais , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Toxina Diftérica/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Linfonodos/imunologia , Linfonodos/metabolismo , Ativação Linfocitária , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Quimiocinas/metabolismo , Linfócitos T Reguladores/imunologia , Microambiente TumoralRESUMO
Although many aspects of blood production are well understood, the spatial organization of myeloid differentiation in the bone marrow remains unknown. Here we use imaging to track granulocyte/macrophage progenitor (GMP) behaviour in mice during emergency and leukaemic myelopoiesis. In the steady state, we find individual GMPs scattered throughout the bone marrow. During regeneration, we observe expanding GMP patches forming defined GMP clusters, which, in turn, locally differentiate into granulocytes. The timed release of important bone marrow niche signals (SCF, IL-1ß, G-CSF, TGFß and CXCL4) and activation of an inducible Irf8 and ß-catenin progenitor self-renewal network control the transient formation of regenerating GMP clusters. In leukaemia, we show that GMP clusters are constantly produced owing to persistent activation of the self-renewal network and a lack of termination cytokines that normally restore haematopoietic stem-cell quiescence. Our results uncover a previously unrecognized dynamic behaviour of GMPs in situ, which tunes emergency myelopoiesis and is hijacked in leukaemia.
Assuntos
Autorrenovação Celular , Células Progenitoras de Granulócitos e Macrófagos/citologia , Células Progenitoras de Granulócitos e Macrófagos/patologia , Leucemia/patologia , Mielopoese , Células-Tronco Neoplásicas/patologia , Animais , Reprogramação Celular , Citocinas/metabolismo , Granulócitos/citologia , Granulócitos/patologia , Fatores Reguladores de Interferon/metabolismo , Macrófagos/citologia , Macrófagos/patologia , Camundongos , Imagem Molecular , Nicho de Células-Tronco/fisiologia , beta Catenina/metabolismoRESUMO
Blood production is ensured by rare, self-renewing haematopoietic stem cells (HSCs). How HSCs accommodate the diverse cellular stresses associated with their life-long activity remains elusive. Here we identify autophagy as an essential mechanism protecting HSCs from metabolic stress. We show that mouse HSCs, in contrast to their short-lived myeloid progeny, robustly induce autophagy after ex vivo cytokine withdrawal and in vivo calorie restriction. We demonstrate that FOXO3A is critical to maintain a gene expression program that poises HSCs for rapid induction of autophagy upon starvation. Notably, we find that old HSCs retain an intact FOXO3A-driven pro-autophagy gene program, and that ongoing autophagy is needed to mitigate an energy crisis and allow their survival. Our results demonstrate that autophagy is essential for the life-long maintenance of the HSC compartment and for supporting an old, failing blood system.
Assuntos
Autofagia/genética , Metabolismo Energético/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Estresse Fisiológico/genética , Envelhecimento , Animais , Apoptose , Restrição Calórica , Sobrevivência Celular/genética , Senescência Celular , Citocinas/deficiência , Citocinas/metabolismo , Privação de Alimentos , Proteína Forkhead Box O3 , Homeostase , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Formation of the vascular system within organs requires the balanced action of numerous positive and negative factors secreted by stromal and epithelial cells. Here, we used a genetic approach to determine the role of SLITs in regulating the growth and organization of blood vessels in the mammary gland. We demonstrate that vascularization of the gland is not affected by loss of Slit expression in the epithelial compartment. Instead, we identify a stromal source of SLIT, mural cells encircling blood vessels, and show that loss of Slit in the stroma leads to elevated blood vessel density and complexity. We examine candidate SLIT receptors, Robo1 and Robo4, and find that increased vessel angiogenesis is phenocopied by loss of endothelial-specific Robo4, as long as it is combined with the presence of an angiogenic stimulus such as preneoplasia or pregnancy. In contrast, loss of Robo1 does not affect blood vessel growth. The enhanced growth of blood vessels in Robo4(-/-) endothelium is due to activation of vascular endothelial growth factor (VEGF)-R2 signaling through the Src and FAK kinases. Thus, our studies present a genetic dissection of SLIT/ROBO signaling during organ development. We identify a stromal, rather than epithelial, source of SLITs that inhibits blood vessel growth by signaling through endothelial ROBO4 to down-regulate VEGF/VEGFR2 signaling.
Assuntos
Glândulas Mamárias Animais/irrigação sanguínea , Glândulas Mamárias Animais/metabolismo , Neovascularização Fisiológica , Proteínas do Tecido Nervoso/metabolismo , Receptores Imunológicos/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/deficiência , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/deficiência , Receptores de Superfície Celular , Receptores Imunológicos/deficiência , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas RoundaboutRESUMO
The development of immune checkpoint-based immunotherapies has been a major advancement in the treatment of cancer, with a subset of patients exhibiting durable clinical responses. A predictive biomarker for immunotherapy response is the preexisting T-cell infiltration in the tumor immune microenvironment (TIME). Bulk transcriptomics-based approaches can quantify the degree of T-cell infiltration using deconvolution methods and identify additional markers of inflamed/cold cancers at the bulk level. However, bulk techniques are unable to identify biomarkers of individual cell types. Although single-cell RNA sequencing (scRNA-seq) assays are now being used to profile the TIME, to our knowledge there is no method of identifying patients with a T-cell inflamed TIME from scRNA-seq data. Here, we describe a method, iBRIDGE, which integrates reference bulk RNA-seq data with the malignant subset of scRNA-seq datasets to identify patients with a T-cell inflamed TIME. Using two datasets with matched bulk data, we show iBRIDGE results correlated highly with bulk assessments (0.85 and 0.9 correlation coefficients). Using iBRIDGE, we identified markers of inflamed phenotypes in malignant cells, myeloid cells, and fibroblasts, establishing type I and type II interferon pathways as dominant signals, especially in malignant and myeloid cells, and finding the TGFß-driven mesenchymal phenotype not only in fibroblasts but also in malignant cells. Besides relative classification, per-patient average iBRIDGE scores and independent RNAScope quantifications were used for threshold-based absolute classification. Moreover, iBRIDGE can be applied to in vitro grown cancer cell lines and can identify the cell lines that are adapted from inflamed/cold patient tumors.
Assuntos
Neoplasias , Análise da Expressão Gênica de Célula Única , Humanos , RNA-Seq/métodos , Perfilação da Expressão Gênica/métodos , Linfócitos T , Biomarcadores , Análise de Célula Única/métodos , Microambiente Tumoral/genéticaRESUMO
Myeloid cells in the tumor microenvironment (TME) can exist in immunosuppressive and immunostimulatory states that impede or promote antitumor immunity, respectively. Blocking suppressive myeloid cells or increasing stimulatory cells to enhance antitumor immune responses is an area of interest for therapeutic intervention. Triggering receptor expressed on myeloid cells-1 (TREM1) is a proinflammatory receptor that amplifies immune responses. TREM1 is expressed on neutrophils, subsets of monocytes and tissue macrophages, and suppressive myeloid populations in the TME, including tumor-associated neutrophils, monocytes, and tumor-associated macrophages. Depletion or inhibition of immunosuppressive myeloid cells, or stimulation by TREM1-mediated inflammatory signaling, could be used to promote an immunostimulatory TME. We developed PY159, an afucosylated humanized anti-TREM1 monoclonal antibody with enhanced FcγR binding. PY159 is a TREM1 agonist that induces signaling, leading to up-regulation of costimulatory molecules on monocytes and macrophages, production of proinflammatory cytokines and chemokines, and enhancement of T cell activation in vitro. An antibody against mouse TREM1, PY159m, promoted antitumor efficacy in syngeneic mouse tumor models. These results suggest that PY159-mediated agonism of TREM1 on tumoral myeloid cells can promote a proinflammatory TME and offer a promising strategy for immunotherapy.
Assuntos
Monócitos , Células Mieloides , Animais , Camundongos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Modelos Animais de Doenças , Imunossupressores , Macrófagos , Receptor Gatilho 1 Expresso em Células MieloidesRESUMO
The tumor immune microenvironment (TIME) is commonly infiltrated by diverse collections of myeloid cells. Yet, the complexity of myeloid-cell identity and plasticity has challenged efforts to define bona fide populations and determine their connections to T-cell function and their relationship to patient outcome. Here, we have leveraged single-cell RNA-sequencing analysis of several mouse and human tumors and found that monocyte-macrophage diversity is characterized by a combination of conserved lineage states as well as transcriptional programs accessed along the differentiation trajectory. We also found in mouse models that tumor monocyte-to-macrophage progression was profoundly tied to regulatory T cell (Treg) abundance. In human kidney cancer, heterogeneity in macrophage accumulation and myeloid composition corresponded to variance in, not only Treg density, but also the quality of infiltrating CD8+ T cells. In this way, holistic analysis of monocyte-to-macrophage differentiation creates a framework for critically different immune states.
Assuntos
Neoplasias Renais , Monócitos , Animais , Macrófagos , Camundongos , Fenótipo , Microambiente TumoralRESUMO
Converting checkpoint inhibitor (CPI)-resistant individuals to being responsive requires identifying suppressive mechanisms. We identify TREM2+ tumor-associated macrophages (TAMs) as being correlated with exhausted CD8+ tumor-infiltrating lymphocytes (TILs) in mouse syngeneic tumor models and human solid tumors of multiple histological types. Fc domain-enhanced anti-TREM2 monoclonal antibody (mAb) therapy promotes anti-tumor immunity by elimination and modulation of TAM populations, which leads to enhanced CD8+ TIL infiltration and effector function. TREM2+ TAMs are most enriched in individuals with ovarian cancer, where TREM2 expression corresponds to disease grade accompanied by worse recurrence-free survival. In an aggressive orthotopic ovarian cancer model, anti-TREM2 mAb therapy drives potent anti-tumor immunity. These results highlight TREM2 as a highly attractive target for immunotherapy modulation in individuals who are refractory to CPI therapy and likely have a TAM-rich tumor microenvironment.
Assuntos
Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Glicoproteínas de Membrana/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Receptores Imunológicos/antagonistas & inibidores , Macrófagos Associados a Tumor/efeitos dos fármacos , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Resistencia a Medicamentos Antineoplásicos , Feminino , Células HEK293 , Humanos , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores Imunológicos/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismoRESUMO
Generation of tumor-infiltrating lymphocytes begins when tumor antigens reach the lymph node (LN) to stimulate T cells, yet we know little of how tumor material is disseminated among the large variety of antigen-presenting dendritic cell (DC) subsets in the LN. Here, we demonstrate that tumor proteins are carried to the LN within discrete vesicles inside DCs and are then transferred among DC subsets. A synapse is formed between interacting DCs and vesicle transfer takes place in the absence of free exosomes. DCs -containing vesicles can uniquely activate T cells, whereas DCs lacking them do not. Understanding this restricted sharing of tumor identity provides substantial room for engineering better anti-tumor immunity.
Assuntos
Apresentação de Antígeno/imunologia , Antígenos de Neoplasias/imunologia , Células Dendríticas/imunologia , Melanoma Experimental/imunologia , Células Mieloides/imunologia , Sinapses/imunologia , Linfócitos T/imunologia , Animais , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Masculino , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/citologia , Células Mieloides/metabolismo , Receptores CCR2/fisiologia , Receptores CCR7/fisiologia , Sinapses/metabolismo , Sinapses/patologia , Linfócitos T/citologia , Linfócitos T/metabolismoRESUMO
The tumor microenvironment (TME) of diverse cancer types is often characterized by high levels of infiltrating myeloid cells including monocytes, macrophages, dendritic cells, and granulocytes. These cells perform a variety of functions in the TME, varying from immune suppressive to immune stimulatory roles. In this review, we summarize the different myeloid cell populations in the TME and the intratumoral myeloid targeting approaches that are being clinically investigated, and discuss strategies that identify new myeloid subpopulations within the TME. The TME therapies include agents that modulate the functional activities of myeloid populations, that impact recruitment and survival of myeloid subpopulations, and that functionally reprogram or activate myeloid populations. We discuss the benefits, limitations and potential side effects of these therapeutic approaches.
Assuntos
Células Mieloides/imunologia , Células Mieloides/metabolismo , Neoplasias/etiologia , Neoplasias/patologia , Microambiente Tumoral , Animais , Biomarcadores , Diferenciação Celular , Proliferação de Células , Sobrevivência Celular , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Imunomodulação , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Microambiente Tumoral/imunologiaRESUMO
The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient's tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.
Assuntos
Imunoterapia , Microambiente Tumoral/imunologia , Genótipo , Humanos , Metástase Neoplásica , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , FenótipoRESUMO
Intratumoral stimulatory dendritic cells (SDCs) play an important role in stimulating cytotoxic T cells and driving immune responses against cancer. Understanding the mechanisms that regulate their abundance in the tumor microenvironment (TME) could unveil new therapeutic opportunities. We find that in human melanoma, SDC abundance is associated with intratumoral expression of the gene encoding the cytokine FLT3LG. FLT3LG is predominantly produced by lymphocytes, notably natural killer (NK) cells in mouse and human tumors. NK cells stably form conjugates with SDCs in the mouse TME, and genetic and cellular ablation of NK cells in mice demonstrates their importance in positively regulating SDC abundance in tumor through production of FLT3L. Although anti-PD-1 'checkpoint' immunotherapy for cancer largely targets T cells, we find that NK cell frequency correlates with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with increased overall survival. Our studies reveal that innate immune SDCs and NK cells cluster together as an excellent prognostic tool for T cell-directed immunotherapy and that these innate cells are necessary for enhanced T cell tumor responses, suggesting this axis as a target for new therapies.
Assuntos
Células Dendríticas/imunologia , Imunoterapia , Células Matadoras Naturais/imunologia , Microambiente Tumoral/imunologia , Antígenos de Superfície/metabolismo , Comunicação Celular , Sobrevivência Celular , Humanos , Linfócitos/metabolismo , Melanoma/imunologia , Melanoma/patologia , Proteínas de Membrana/metabolismo , Análise de Sobrevida , TrombomodulinaRESUMO
Intratumoral dendritic cells (DC) bearing CD103 in mice or CD141 in humans drive intratumoral CD8(+) T cell activation. Using multiple strategies, we identified a critical role for these DC in trafficking tumor antigen to lymph nodes (LN), resulting in both direct CD8(+) T cell stimulation and antigen hand-off to resident myeloid cells. These effects all required CCR7. Live imaging demonstrated direct presentation to T cells in LN, and CCR7 loss specifically in these cells resulted in defective LN T cell priming and increased tumor outgrowth. CCR7 expression levels in human tumors correlate with signatures of CD141(+) DC, intratumoral T cells, and better clinical outcomes. This work identifies an ongoing pathway to T cell priming, which should be harnessed for tumor therapies.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Melanoma/imunologia , Receptores CCR7/imunologia , Animais , Apresentação de Antígeno , Antígenos CD/imunologia , Antígenos de Neoplasias/imunologia , Antígenos de Superfície/imunologia , Movimento Celular/imunologia , Células Dendríticas/patologia , Humanos , Cadeias alfa de Integrinas/imunologia , Linfonodos/imunologia , Linfonodos/patologia , Melanoma/patologia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , TrombomodulinaRESUMO
Type I interferons (IFN-1s) are antiviral cytokines that suppress blood production while paradoxically inducing hematopoietic stem cell (HSC) proliferation. Here, we clarify the relationship between the proliferative and suppressive effects of IFN-1s on HSC function during acute and chronic IFN-1 exposure. We show that IFN-1-driven HSC proliferation is a transient event resulting from a brief relaxation of quiescence-enforcing mechanisms in response to acute IFN-1 exposure, which occurs exclusively in vivo. We find that this proliferative burst fails to exhaust the HSC pool, which rapidly returns to quiescence in response to chronic IFN-1 exposure. Moreover, we demonstrate that IFN-1-exposed HSCs with reestablished quiescence are largely protected from the killing effects of IFNs unless forced back into the cell cycle due to culture, transplantation, or myeloablative treatment, at which point they activate a p53-dependent proapoptotic gene program. Collectively, our results demonstrate that quiescence acts as a safeguard mechanism to ensure survival of the HSC pool during chronic IFN-1 exposure. We show that IFN-1s can poise HSCs for apoptosis but induce direct cell killing only upon active proliferation, thereby establishing a mechanism for the suppressive effects of IFN-1s on HSC function.
Assuntos
Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Interferon Tipo I/fisiologia , Animais , Apoptose/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Hematopoese/efeitos dos fármacos , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Interferon Tipo I/administração & dosagem , Masculino , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Transdução de Sinais , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/fisiologiaRESUMO
It is well understood that antigen-presenting cells (APCs) within tumors typically do not maintain cytotoxic T cell (CTL) function, despite engaging them. Across multiple mouse tumor models and human tumor biopsies, we have delineated the intratumoral dendritic cell (DC) populations as distinct from macrophage populations. Within these, CD103(+) DCs are extremely sparse and yet remarkably capable CTL stimulators. These are uniquely dependent on IRF8, Zbtb46, and Batf3 transcription factors and are generated by GM-CSF and FLT3L cytokines. Regressing tumors have higher proportions of these cells, T-cell-dependent immune clearance relies on them, and abundance of their transcripts in human tumors correlates with clinical outcome. This cell type presents opportunities for prognostic and therapeutic approaches across multiple cancer types.
Assuntos
Células Dendríticas/imunologia , Neoplasias Mamárias Experimentais/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD/metabolismo , Técnicas de Cocultura , Células Dendríticas/metabolismo , Feminino , Humanos , Imunoterapia Adotiva , Macrófagos/metabolismo , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos Endogâmicos C57BL , Células Mieloides/imunologia , Células Mieloides/metabolismo , Linfócitos T/metabolismo , Células Tumorais Cultivadas , Microambiente TumoralRESUMO
Multipotent stromal cells (MSCs) and their osteoblastic lineage cell (OBC) derivatives are part of the bone marrow (BM) niche and contribute to hematopoietic stem cell (HSC) maintenance. Here, we show that myeloproliferative neoplasia (MPN) progressively remodels the endosteal BM niche into a self-reinforcing leukemic niche that impairs normal hematopoiesis, favors leukemic stem cell (LSC) function, and contributes to BM fibrosis. We show that leukemic myeloid cells stimulate MSCs to overproduce functionally altered OBCs, which accumulate in the BM cavity as inflammatory myelofibrotic cells. We identify roles for thrombopoietin, CCL3, and direct cell-cell interactions in driving OBC expansion, and for changes in TGF-ß, Notch, and inflammatory signaling in OBC remodeling. MPN-expanded OBCs, in turn, exhibit decreased expression of many HSC retention factors and severely compromised ability to maintain normal HSCs, but effectively support LSCs. Targeting this pathological interplay could represent a novel avenue for treatment of MPN-affected patients and prevention of myelofibrosis.
Assuntos
Medula Óssea/fisiologia , Leucemia/fisiopatologia , Células-Tronco Mesenquimais/fisiologia , Transtornos Mieloproliferativos/fisiopatologia , Células-Tronco Neoplásicas/fisiologia , Mielofibrose Primária/fisiopatologia , Nicho de Células-Tronco , Animais , Transdiferenciação Celular , Células Cultivadas , Quimiocina CCL3/metabolismo , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia/complicações , Leucemia/patologia , Camundongos , Camundongos Transgênicos , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/patologia , Mielofibrose Primária/etiologia , Receptores Notch/metabolismo , Trombopoetina/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Using a mouse model recapitulating the main features of human chronic myelogenous leukemia (CML), we uncover the hierarchy of leukemic stem and progenitor cells contributing to disease pathogenesis. We refine the characterization of CML leukemic stem cells (LSCs) to the most immature long-term hematopoietic stem cells (LT-HSCs) and identify some important molecular deregulations underlying their aberrant behavior. We find that CML multipotent progenitors (MPPs) exhibit an aberrant B-lymphoid potential but are redirected toward the myeloid lineage by the action of the proinflammatory cytokine IL-6. We show that BCR/ABL activity controls Il-6 expression thereby establishing a paracrine feedback loop that sustains CML development. These results describe how proinflammatory tumor environment affects leukemic progenitor cell fate and contributes to CML pathogenesis.
Assuntos
Interleucina-6/fisiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células-Tronco Multipotentes/patologia , Animais , Retroalimentação Fisiológica , Proteínas de Fusão bcr-abl/metabolismo , Proteínas de Fusão bcr-abl/fisiologia , Interleucina-6/genética , Interleucina-6/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Camundongos , Células Precursoras de Linfócitos B/metabolismo , Células Precursoras de Linfócitos B/patologiaRESUMO
The genes encoding Slits and their Robo receptors are silenced in many types of cancer, including breast, suggesting a role for this signaling pathway in suppressing tumorigenesis. The molecular mechanism underlying these tumor-suppressive effects has not been delineated. Here, we show that loss of Slits, or their Robo1 receptor, in murine mammary gland or human breast carcinoma cells results in coordinate up-regulation of the Sdf1 and Cxcr4 signaling axis, specifically within mammary epithelium. This is accompanied by hyperplastic changes in cells and desmoplastic alterations in the surrounding stroma. A similar inverse correlation between Slit and Cxcr4 expression is identified in human breast tumor tissues. Furthermore, we show in a xenograft model that Slit overexpression down-regulates CXCR4 and dominantly suppresses tumor growth. These studies classify Slits as negative regulators of Sdf1 and Cxcr4 and identify a molecular signature in hyperplastic breast lesions that signifies inappropriate up-regulation of key prometastatic genes.