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1.
Nat Biomed Eng ; 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38710838

RESUMO

Following immunization, lymph nodes dynamically expand and contract. The mechanical and cellular changes enabling the early-stage expansion of lymph nodes have been characterized, yet the durability of such responses and their implications for adaptive immunity and vaccine efficacy are unknown. Here, by leveraging high-frequency ultrasound imaging of the lymph nodes of mice, we report more potent and persistent lymph-node expansion for animals immunized with a mesoporous silica vaccine incorporating a model antigen than for animals given bolus immunization or standard vaccine formulations such as alum, and that durable and robust lymph-node expansion was associated with vaccine efficacy and adaptive immunity for 100 days post-vaccination in a mouse model of melanoma. Immunization altered the mechanical and extracellular-matrix properties of the lymph nodes, drove antigen-dependent proliferation of immune and stromal cells, and altered the transcriptional features of dendritic cells and inflammatory monocytes. Strategies that robustly maintain lymph-node expansion may result in enhanced vaccination outcomes.

2.
Immunity ; 56(10): 2188-2205, 2023 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-37820582

RESUMO

The cancer-immunity cycle provides a framework to understand the series of events that generate anti-cancer immune responses. It emphasizes the iterative nature of the response where the killing of tumor cells by T cells initiates subsequent rounds of antigen presentation and T cell stimulation, maintaining active immunity and adapting it to tumor evolution. Any step of the cycle can become rate-limiting, rendering the immune system unable to control tumor growth. Here, we update the cancer-immunity cycle based on the remarkable progress of the past decade. Understanding the mechanism of checkpoint inhibition has evolved, as has our view of dendritic cells in sustaining anti-tumor immunity. We additionally account for the role of the tumor microenvironment in facilitating, not just suppressing, the anti-cancer response, and discuss the importance of considering a tumor's immunological phenotype, the "immunotype". While these new insights add some complexity to the cycle, they also provide new targets for research and therapeutic intervention.


Assuntos
Imunoterapia , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Neoplasias/metabolismo , Linfócitos T , Apresentação de Antígeno , Genótipo , Microambiente Tumoral/genética
3.
Cell Rep Med ; 4(10): 101232, 2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37852182

RESUMO

In this issue of Cell Reports Medicine, Qin et al.1 present a comprehensive single-cell transcriptomics analysis of the tumor microenvironment of rectal cancer tumors before and after neoadjuvant chemotherapy.


Assuntos
Terapia Neoadjuvante , Neoplasias Retais , Humanos , Estadiamento de Neoplasias , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Microambiente Tumoral
4.
Nat Commun ; 14(1): 4703, 2023 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-37543621

RESUMO

TGFß signaling is associated with non-response to immune checkpoint blockade in patients with advanced cancers, particularly in the immune-excluded phenotype. While previous work demonstrates that converting tumors from excluded to inflamed phenotypes requires attenuation of PD-L1 and TGFß signaling, the underlying cellular mechanisms remain unclear. Here, we show that TGFß and PD-L1 restrain intratumoral stem cell-like CD8 T cell (TSCL) expansion and replacement of progenitor-exhausted and dysfunctional CD8 T cells with non-exhausted T effector cells in the EMT6 tumor model in female mice. Upon combined TGFß/PD-L1 blockade IFNγhi CD8 T effector cells show enhanced motility and accumulate in the tumor. Ensuing IFNγ signaling transforms myeloid, stromal, and tumor niches to yield an immune-supportive ecosystem. Blocking IFNγ abolishes the anti-PD-L1/anti-TGFß therapy efficacy. Our data suggest that TGFß works with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells, thereby maintaining the T cell compartment in a dysfunctional state.


Assuntos
Antígeno B7-H1 , Neoplasias da Mama , Linfócitos T CD8-Positivos , Inibidores de Checkpoint Imunológico , Fator de Crescimento Transformador beta , Feminino , Animais , Camundongos , Diferenciação Celular , Linfócitos T CD8-Positivos/imunologia , Células-Tronco , Antígeno B7-H1/antagonistas & inibidores , Fator de Crescimento Transformador beta/antagonistas & inibidores , Interferon gama/imunologia , Exaustão das Células T , Inibidores de Checkpoint Imunológico/farmacologia , Camundongos Endogâmicos BALB C , Linhagem Celular Tumoral , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , RNA-Seq
5.
Nature ; 618(7966): 827-833, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37258670

RESUMO

The immune phenotype of a tumour is a key predictor of its response to immunotherapy1-4. Patients who respond to checkpoint blockade generally present with immune-inflamed5-7 tumours that are highly infiltrated by T cells. However, not all inflamed tumours respond to therapy, and even lower response rates occur among tumours that lack T cells (immune desert) or that spatially exclude T cells to the periphery of the tumour lesion (immune excluded)8. Despite the importance of these tumour immune phenotypes in patients, little is known about their development, heterogeneity or dynamics owing to the technical difficulty of tracking these features in situ. Here we introduce skin tumour array by microporation (STAMP)-a preclinical approach that combines high-throughput time-lapse imaging with next-generation sequencing of tumour arrays. Using STAMP, we followed the development of thousands of arrayed tumours in vivo to show that tumour immune phenotypes and outcomes vary between adjacent tumours and are controlled by local factors within the tumour microenvironment. Particularly, the recruitment of T cells by fibroblasts and monocytes into the tumour core was supportive of T cell cytotoxic activity and tumour rejection. Tumour immune phenotypes were dynamic over time and an early conversion to an immune-inflamed phenotype was predictive of spontaneous or therapy-induced tumour rejection. Thus, STAMP captures the dynamic relationships of the spatial, cellular and molecular components of tumour rejection and has the potential to translate therapeutic concepts into successful clinical strategies.


Assuntos
Neoplasias , Linfócitos T , Microambiente Tumoral , Humanos , Imunoterapia , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Linfócitos T/imunologia , Fenótipo , Fibroblastos , Monócitos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico
6.
Eur J Immunol ; 53(9): e2250355, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-36991561

RESUMO

The lymph node (LN) is home to resident macrophage populations that are essential for immune function and homeostasis, but key factors controlling this niche are undefined. Here, we show that fibroblastic reticular cells (FRCs) are an essential component of the LN macrophage niche. Genetic ablation of FRCs caused rapid loss of macrophages and monocytes from LNs across two in vivo models. Macrophages co-localized with FRCs in human LNs, and murine single-cell RNA-sequencing revealed that FRC subsets broadly expressed master macrophage regulator CSF1. Functional assays containing purified FRCs and monocytes showed that CSF1R signaling was sufficient to support macrophage development. These effects were conserved between mouse and human systems. These data indicate an important role for FRCs in maintaining the LN parenchymal macrophage niche.


Assuntos
Fibroblastos , Transdução de Sinais , Camundongos , Humanos , Animais , Macrófagos , Linfonodos
7.
Cell Rep Med ; 4(1): 100878, 2023 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-36599350

RESUMO

Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming therapeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder cancers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8+ cytotoxic T lymphocyte (CTL) responses compared with anti-PD-L1 alone. Circulating CTLs from cancer patients with high plasma IL-6 display a repressed functional profile based on single-cell RNA sequencing, and IL-6-STAT3 signaling inhibits classical cytotoxic differentiation of CTLs in vitro. In tumor-bearing mice, CTL-specific IL6R deficiency is sufficient to improve anti-PD-L1 activity. Thus, based on both clinical and experimental evidence, agents targeting IL-6 signaling are plausible partners for combination with ICIs in cancer patients.


Assuntos
Antineoplásicos , Interleucina-6 , Neoplasias , Animais , Camundongos , Antineoplásicos/uso terapêutico , Antígeno B7-H1/imunologia , Antígeno B7-H1/uso terapêutico , Linfócitos T CD8-Positivos/metabolismo , Imunoterapia , Interleucina-6/metabolismo , Neoplasias/imunologia , Neoplasias/terapia
8.
Nature ; 611(7934): 148-154, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36171287

RESUMO

Recent single-cell studies of cancer in both mice and humans have identified the emergence of a myofibroblast population specifically marked by the highly restricted leucine-rich-repeat-containing protein 15 (LRRC15)1-3. However, the molecular signals that underlie the development of LRRC15+ cancer-associated fibroblasts (CAFs) and their direct impact on anti-tumour immunity are uncharacterized. Here in mouse models of pancreatic cancer, we provide in vivo genetic evidence that TGFß receptor type 2 signalling in healthy dermatopontin+ universal fibroblasts is essential for the development of cancer-associated LRRC15+ myofibroblasts. This axis also predominantly drives fibroblast lineage diversity in human cancers. Using newly developed Lrrc15-diphtheria toxin receptor knock-in mice to selectively deplete LRRC15+ CAFs, we show that depletion of this population markedly reduces the total tumour fibroblast content. Moreover, the CAF composition is recalibrated towards universal fibroblasts. This relieves direct suppression of tumour-infiltrating CD8+ T cells to enhance their effector function and augments tumour regression in response to anti-PDL1 immune checkpoint blockade. Collectively, these findings demonstrate that TGFß-dependent LRRC15+ CAFs dictate the tumour-fibroblast setpoint to promote tumour growth. These cells also directly suppress CD8+ T cell function and limit responsiveness to checkpoint blockade. Development of treatments that restore the homeostatic fibroblast setpoint by reducing the population of pro-disease LRRC15+ myofibroblasts may improve patient survival and response to immunotherapy.


Assuntos
Fibroblastos Associados a Câncer , Proteínas de Membrana , Miofibroblastos , Neoplasias Pancreáticas , Células Estromais , Animais , Humanos , Camundongos , Fibroblastos Associados a Câncer/metabolismo , Linfócitos T CD8-Positivos/imunologia , Proteínas de Membrana/metabolismo , Miofibroblastos/metabolismo , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Receptores de Fatores de Crescimento Transformadores beta , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral , Antígeno B7-H1
9.
Cancer Discov ; 12(11): 2606-2625, 2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-36027053

RESUMO

It is currently accepted that cancer-associated fibroblasts (CAF) participate in T-cell exclusion from tumor nests. To unbiasedly test this, we used single-cell RNA sequencing coupled with multiplex imaging on a large cohort of lung tumors. We identified four main CAF populations, two of which are associated with T-cell exclusion: (i) MYH11+αSMA+ CAF, which are present in early-stage tumors and form a single cell layer lining cancer aggregates, and (ii) FAP+αSMA+ CAF, which appear in more advanced tumors and organize in patches within the stroma or in multiple layers around tumor nests. Both populations orchestrate a particular structural tissue organization through dense and aligned fiber deposition compared with T cell-permissive CAF. Yet they produce distinct matrix molecules, including collagen IV (MYH11+αSMA+ CAF) and collagen XI/XII (FAP+αSMA+ CAF). Hereby, we uncovered unique molecular programs of CAF driving T-cell marginalization, whose targeting should increase immunotherapy efficacy in patients bearing T cell-excluded tumors. SIGNIFICANCE: The cellular and molecular programs driving T-cell marginalization in solid tumors remain unclear. Here, we describe two CAF populations associated with T-cell exclusion in human lung tumors. We demonstrate the importance of pairing molecular and spatial analysis of the tumor microenvironment, a prerequisite to developing new strategies targeting T cell-excluding CAF. See related commentary by Sherman, p. 2501. This article is highlighted in the In This Issue feature, p. 2483.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias Pulmonares , Humanos , Fibroblastos Associados a Câncer/patologia , Linfócitos T , Microambiente Tumoral , Imunoterapia/métodos , Neoplasias Pulmonares/patologia , Fibroblastos
10.
J Exp Med ; 219(10)2022 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-35980386

RESUMO

Recent studies have defined a novel population of PD-1+ TCF-1+ stem-like CD8 T cells in chronic infections and cancer. These quiescent cells reside in lymphoid tissues, are critical for maintaining the CD8 T cell response under conditions of persistent antigen, and provide the proliferative burst after PD-1 blockade. Here we examined the role of TGF-ß in regulating the differentiation of virus-specific CD8 T cells during chronic LCMV infection of mice. We found that TGF-ß signaling was not essential for the generation of the stem-like CD8 T cells but was critical for maintaining the stem-like state and quiescence of these cells. TGF-ß regulated the unique transcriptional program of the stem-like subset, including upregulation of inhibitory receptors specifically expressed on these cells. TGF-ß also promoted the terminal differentiation of exhausted CD8 T cells by suppressing the effector-associated program. Together, the absence of TGF-ß signaling resulted in significantly increased accumulation of effector-like CD8 T cells. These findings have implications for immunotherapies in general and especially for T cell therapy against chronic infections and cancer.


Assuntos
Coriomeningite Linfocítica , Neoplasias , Animais , Linfócitos T CD8-Positivos , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos , Infecção Persistente , Receptor de Morte Celular Programada 1 , Fator de Crescimento Transformador beta
11.
Cancer Cell ; 40(6): 656-673.e7, 2022 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-35523176

RESUMO

Recent studies have identified a unique cancer-associated fibroblast (CAF) population termed antigen-presenting CAFs (apCAFs), characterized by the expression of major histocompatibility complex class II molecules, suggesting a function in regulating tumor immunity. Here, by integrating multiple single-cell RNA-sequencing studies and performing robust lineage-tracing assays, we find that apCAFs are derived from mesothelial cells. During pancreatic cancer progression, mesothelial cells form apCAFs by downregulating mesothelial features and gaining fibroblastic features, a process induced by interleukin-1 and transforming growth factor ß. apCAFs directly ligate and induce naive CD4+ T cells into regulatory T cells (Tregs) in an antigen-specific manner. Moreover, treatment with an antibody targeting the mesothelial cell marker mesothelin can effectively inhibit mesothelial cell to apCAF transition and Treg formation induced by apCAFs. Taken together, our study elucidates how mesothelial cells may contribute to immune evasion in pancreatic cancer and provides insight on strategies to enhance cancer immune therapy.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias Pancreáticas , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos , Humanos , Neoplasias Pancreáticas/patologia , Linfócitos T Reguladores , Fator de Crescimento Transformador beta/metabolismo , Neoplasias Pancreáticas
12.
PLoS One ; 16(12): e0260800, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34879110

RESUMO

The cancer-associated fibroblast (CAF) marker podoplanin (PDPN) is generally correlated with poor clinical outcomes in cancer patients and thus represents a promising therapeutic target. Despite its biomedical relevance, basic aspects of PDPN biology such as its cellular functions and cell surface ligands remain poorly uncharacterized, thus challenging drug development. Here, we utilize a high throughput platform to elucidate the PDPN cell surface interactome, and uncover the neutrophil protein CD177 as a new binding partner. Quantitative proteomics analysis of the CAF phosphoproteome reveals a role for PDPN in cell signaling, growth and actomyosin contractility, among other processes. Moreover, cellular assays demonstrate that CD177 is a functional antagonist, recapitulating the phenotype observed in PDPN-deficient CAFs. In sum, starting from the unbiased elucidation of the PDPN co-receptome, our work provides insights into PDPN functions and reveals the PDPN/CD177 axis as a possible modulator of fibroblast physiology in the tumor microenvironment.


Assuntos
Biomarcadores Tumorais/metabolismo , Fibroblastos Associados a Câncer/patologia , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Isoantígenos/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores de Superfície Celular/metabolismo , Microambiente Tumoral , Apoptose , Biomarcadores Tumorais/genética , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/metabolismo , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Humanos , Isoantígenos/genética , Glicoproteínas de Membrana/genética , Neutrófilos/imunologia , Neutrófilos/metabolismo , Prognóstico , Receptores de Superfície Celular/genética , Taxa de Sobrevida , Células Tumorais Cultivadas
14.
Immunity ; 54(7): 1511-1526.e8, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34260887

RESUMO

Myeloid cells encounter stromal cells and their matrix determinants on a continual basis during their residence in any given organ. Here, we examined the impact of the collagen receptor LAIR1 on myeloid cell homeostasis and function. LAIR1 was highly expressed in the myeloid lineage and enriched in non-classical monocytes. Proteomic definition of the LAIR1 interactome identified stromal factor Colec12 as a high-affinity LAIR1 ligand. Proteomic profiling of LAIR1 signaling triggered by Collagen1 and Colec12 highlighted pathways associated with survival, proliferation, and differentiation. Lair1-/- mice had reduced frequencies of Ly6C- monocytes, which were associated with altered proliferation and apoptosis of non-classical monocytes from bone marrow and altered heterogeneity of interstitial macrophages in lung. Myeloid-specific LAIR1 deficiency promoted metastatic growth in a melanoma model and LAIR1 expression associated with improved clinical outcomes in human metastatic melanoma. Thus, monocytes and macrophages rely on LAIR1 sensing of stromal determinants for fitness and function, with relevance in homeostasis and disease.


Assuntos
Homeostase/fisiologia , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Monócitos/metabolismo , Receptores Imunológicos/metabolismo , Animais , Apoptose/fisiologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Células COS , Diferenciação Celular/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Linhagem da Célula/fisiologia , Proliferação de Células/fisiologia , Chlorocebus aethiops , Feminino , Humanos , Pulmão/patologia , Macrófagos Alveolares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/patologia , Células Mieloides/metabolismo , Células Mieloides/patologia , Metástase Neoplásica/patologia , Proteômica/métodos , Transdução de Sinais/fisiologia
15.
Immunol Rev ; 302(1): 299-320, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34164824

RESUMO

Fibroblasts, custodians of tissue architecture and function, are no longer considered a monolithic entity across tissues and disease indications. Recent advances in single-cell technologies provide an unrestricted, high-resolution view of fibroblast heterogeneity that exists within and across tissues. In this review, we summarize a compendium of single-cell transcriptomic studies and provide a comprehensive accounting of fibroblast subsets, many of which have been described to occupy specific niches in tissues at homeostatic and pathologic states. Understanding this heterogeneity is particularly important in the context of cancer, as the diverse cancer-associated fibroblast (CAF) phenotypes in the tumor microenvironment (TME) are directly impacted by the expression phenotypes of their predecessors. Relationships between these heterogeneous populations often accompany and influence response to therapy in cancer and fibrosis. We further highlight the importance of integrating single-cell studies to deduce common fibroblast phenotypes across disease states, which will facilitate the identification of common signaling pathways, gene regulatory programs, and cell surface markers that are going to advance drug discovery and targeting.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias , Biomarcadores , Fibroblastos , Humanos , Neoplasias/genética , Neoplasias/terapia , Microambiente Tumoral
16.
Cancer Cell ; 39(7): 928-944.e6, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-33961783

RESUMO

Distinct T cell infiltration patterns, i.e., immune infiltrated, excluded, and desert, result in different responses to cancer immunotherapies. However, the key determinants and biology underpinning these tumor immune phenotypes remain elusive. Here, we provide a high-resolution dissection of the entire tumor ecosystem through single-cell RNA-sequencing analysis of 15 ovarian tumors. Immune-desert tumors are characterized by unique tumor cell-intrinsic features, including metabolic pathways and low antigen presentation, and an enrichment of monocytes and immature macrophages. Immune-infiltrated and -excluded tumors differ markedly in their T cell composition and fibroblast subsets. Furthermore, our study reveals chemokine receptor-ligand interactions within and across compartments as potential mechanisms mediating immune cell infiltration, exemplified by the tumor cell-T cell cross talk via CXCL16-CXCR6 and stromal-immune cell cross talk via CXCL12/14-CXCR4. Our data highlight potential molecular mechanisms that shape the tumor immune phenotypes and may inform therapeutic strategies to improve clinical benefit from cancer immunotherapies.


Assuntos
Biomarcadores Tumorais/genética , Fibroblastos/imunologia , Neoplasias Ovarianas/imunologia , Análise de Célula Única/métodos , Células Estromais/imunologia , Linfócitos T/imunologia , Microambiente Tumoral , Biomarcadores Tumorais/imunologia , Quimiocina CXCL12/genética , Quimiocina CXCL12/imunologia , Quimiocina CXCL16/genética , Quimiocina CXCL16/imunologia , Quimiocinas CXC/genética , Quimiocinas CXC/imunologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , RNA-Seq , Receptores CXCR4/genética , Receptores CXCR4/imunologia , Receptores CXCR6/genética , Receptores CXCR6/imunologia , Células Estromais/metabolismo , Células Estromais/patologia , Linfócitos T/metabolismo , Linfócitos T/patologia
17.
Sci Immunol ; 6(59)2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33963061

RESUMO

Repair of the intestinal epithelium is tightly regulated to maintain homeostasis. The response after epithelial damage needs to be local and proportional to the insult. How different types of damage are coupled to repair remains incompletely understood. We report that after distinct types of intestinal epithelial damage, IL-1R1 signaling in GREM1+ mesenchymal cells increases production of R-spondin 3 (RSPO3), a Wnt agonist required for intestinal stem cell self-renewal. In parallel, IL-1R1 signaling regulates IL-22 production by innate lymphoid cells and promotes epithelial hyperplasia and regeneration. Although the regulation of both RSPO3 and IL-22 is critical for epithelial recovery from Citrobacter rodentium infection, IL-1R1-dependent RSPO3 production by GREM1+ mesenchymal cells alone is sufficient and required for recovery after dextran sulfate sodium-induced colitis. These data demonstrate how IL-1R1-dependent signaling orchestrates distinct repair programs tailored to the type of injury sustained that are required to restore intestinal epithelial barrier function.


Assuntos
Citrobacter rodentium , Infecções por Enterobacteriaceae/imunologia , Mucosa Intestinal/fisiologia , Receptores Tipo I de Interleucina-1/imunologia , Animais , Células Cultivadas , Técnicas de Cocultura , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Sulfato de Dextrana , Células Epiteliais , Fibroblastos , Interleucinas/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Camundongos Transgênicos , Organoides , Receptores Tipo I de Interleucina-1/genética , Regeneração , Transdução de Sinais , Trombospondinas/imunologia , Interleucina 22
18.
Nature ; 593(7860): 575-579, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33981032

RESUMO

Fibroblasts are non-haematopoietic structural cells that define the architecture of organs, support the homeostasis of tissue-resident cells and have key roles in fibrosis, cancer, autoimmunity and wound healing1. Recent studies have described fibroblast heterogeneity within individual tissues1. However, the field lacks a characterization of fibroblasts at single-cell resolution across tissues in healthy and diseased organs. Here we constructed fibroblast atlases by integrating single-cell transcriptomic data from about 230,000 fibroblasts across 17 tissues, 50 datasets, 11 disease states and 2 species. Mouse fibroblast atlases and a DptIRESCreERT2 knock-in mouse identified two universal fibroblast transcriptional subtypes across tissues. Our analysis suggests that these cells can serve as a reservoir that can yield specialized fibroblasts across a broad range of steady-state tissues and activated fibroblasts in disease. Comparison to an atlas of human fibroblasts from perturbed states showed that fibroblast transcriptional states are conserved between mice and humans, including universal fibroblasts and activated phenotypes associated with pathogenicity in human cancer, fibrosis, arthritis and inflammation. In summary, a cross-species and pan-tissue approach to transcriptomics at single-cell resolution has identified key organizing principles of the fibroblast lineage in health and disease.


Assuntos
Fibroblastos/citologia , Transcriptoma , Animais , Células Cultivadas , Doença , Feminino , Fibroblastos/classificação , Técnicas de Introdução de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias , Especificidade de Órgãos , Fenótipo , RNA-Seq , Análise de Célula Única , Células Estromais
19.
Immunity ; 54(5): 903-915, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33979587

RESUMO

Fibroblasts and macrophages are present in all tissues, and mounting evidence supports that these cells engage in direct communication to influence the overall tissue microenvironment and affect disease outcomes. Here, we review the current understanding of the molecular mechanisms that underlie fibroblast-macrophage interactions in health, fibrosis, and cancer. We present an integrated view of fibroblast-macrophage interactions that is centered on the CSF1-CSF1R axis and discuss how additional molecular programs linking these cell types can underpin disease onset, progression, and resolution. These programs may be tissue and context dependent, affected also by macrophage and fibroblast origin and state, as seen most clearly in cancer. Continued efforts to understand these cells and the means by which they interact may provide therapeutic approaches for the treatment of fibrosis and cancer.


Assuntos
Fibroblastos/metabolismo , Fibrose/metabolismo , Macrófagos/metabolismo , Neoplasias/metabolismo , Animais , Diferenciação Celular/fisiologia , Humanos , Fator Estimulador de Colônias de Macrófagos/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Microambiente Tumoral/fisiologia
20.
Nat Rev Immunol ; 21(11): 704-717, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33911232

RESUMO

In chronic infection, inflammation and cancer, the tissue microenvironment controls how local immune cells behave, with tissue-resident fibroblasts emerging as a key cell type in regulating activation or suppression of an immune response. Fibroblasts are heterogeneous cells, encompassing functionally distinct populations, the phenotypes of which differ according to their tissue of origin and type of inciting disease. Their immunological properties are also diverse, ranging from the maintenance of a potent inflammatory environment in chronic inflammation to promoting immunosuppression in malignancy, and encapsulating and incarcerating infectious agents within tissues. In this Review, we compare the mechanisms by which fibroblasts control local immune responses, as well as the factors regulating their inflammatory and suppressive profiles, in different tissues and pathological settings. This cross-disease perspective highlights the importance of tissue context in determining fibroblast-immune cell interactions, as well as potential therapeutic avenues to exploit this knowledge for the benefit of patients with chronic infection, inflammation and cancer.


Assuntos
Fibroblastos/imunologia , Inflamação/imunologia , Neoplasias/imunologia , Infecção Persistente/imunologia , Animais , Humanos , Tolerância Imunológica , Microambiente Tumoral
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