RESUMO
Efficient priming of anti-tumor T cells requires the uptake and presentation of tumor antigens by immunogenic dendritic cells (DCs) and occurs mainly in lymph nodes draining the tumor (tdLNs). However, tumors expand and activate myeloid-derived suppressor cells (MDSCs) that inhibit CTL functions by several mechanisms. While the immune-suppressive nature of the tumor microenvironment is largely documented, it is not known whether similar immune-suppressive mechanisms operate in the tdLNs. In this study, we analyzed MDSC characteristics within tdLNs. We show that, in a metastasis-free context, MO-MDSCs are the dominant MDSC population within tdLNs, that they are highly suppressive and that tumor proximity enhances their recruitment to tdLN via a CCR2/CCL2-dependent pathway. Altogether our results uncover a mechanism by which tumors evade the immune system that involves MDSC-mediated recruitment to the tdLN and the inhibition of T-cell activation even before reaching the highly immunosuppressive tumor microenvironment.
Assuntos
Células Supressoras Mieloides/metabolismo , Receptores CCR2/metabolismo , Microambiente Tumoral/imunologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Linfonodos/metabolismo , Linfonodos/fisiologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Células Mieloides/imunologia , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/fisiologia , Neoplasias/imunologia , Receptores CCR2/imunologiaRESUMO
The tumor-promoting role of macrophages has been firmly established in most cancer types. However, macrophage identity has been a matter of debate, since several levels of complexity result in considerable macrophage heterogeneity. Ontogenically, tissue-resident macrophages derive from yolk sac progenitors which either directly or via a fetal liver monocyte intermediate differentiate into distinct macrophage types during embryogenesis and are maintained throughout life, while a disruption of the steady state mobilizes monocytes and instructs the formation of monocyte-derived macrophages. Histologically, the macrophage phenotype is heavily influenced by the tissue microenvironment resulting in molecularly and functionally distinct macrophages in distinct organs. Finally, a change in the tissue microenvironment as a result of infectious or sterile inflammation instructs different modes of macrophage activation. These considerations are relevant in the context of tumors, which can be considered as sites of chronic sterile inflammation encompassing subregions with distinct environmental conditions (for example, hypoxic versus normoxic). Here, we discuss existing evidence on the role of macrophage subpopulations in steady state tissue and primary tumors of the breast, lung, pancreas, brain and liver.
Assuntos
Macrófagos/fisiologia , Monócitos/citologia , Neoplasias/imunologia , Microambiente Tumoral , Animais , HumanosRESUMO
Monocytes consist of two well-defined subsets, the Ly6C+ and Ly6C- monocytes. Both CD11b+ myeloid cells populations have been proposed to infiltrate tissues during inflammation. While infiltration of Ly6C+ monocytes is an established pathogenic factor during hepatic inflammation, the role of Ly6C- monocytes remains elusive. Mice suffering experimental African trypanosome infection die from systemic inflammatory response syndrome (SIRS) that is initiated by phagocytosis of parasites by liver myeloid cells and culminates in apoptosis/necrosis of liver myeloid and parenchymal cells that reduces host survival. C57BL/6 mice are considered as trypanotolerant to Trypanosoma congolense infection. We have reported that in these animals, IL-10, produced among others by myeloid cells, limits the liver damage caused by pathogenic TNF-producing Ly6C+ monocytes, ensuring prolonged survival. Here, the heterogeneity and dynamics of liver myeloid cells in T. congolense-infected C57/BL6 mice was further dissected. Moreover, the contribution of Ly6C- monocytes to trypanotolerance was investigated. By using FACS analysis and adoptive transfer experiments, we found that the accumulation of Ly6C- monocytes and macrophages in the liver of infected mice coincided with a drop in the pool of Ly6C+ monocytes. Pathogenic TNF mainly originated from Ly6C+ monocytes while Ly6C- monocytes and macrophages were major and equipotent sources of IL-10 within myeloid cells. Moreover, Nr4a1 (Nur77) transcription factor-dependent Ly6C- monocytes exhibited IL-10-dependent and cell contact-dependent regulatory properties contributing to trypanotolerance by suppressing the production of TNF by Ly6C+ monocytes and by promoting the differentiation of the latter cells into macrophages. Thus, Ly6C- monocytes can dampen liver damage caused by an extensive Ly6C+ monocyte-associated inflammatory immune response in T. congolense trypanotolerant animals. In a more general context, Ly6C- or Ly6C+ monocyte targeting may represent a therapeutic approach in liver pathogenicity induced by chronic infection.
Assuntos
Antígenos Ly/imunologia , Diferenciação Celular , Inflamação/etiologia , Hepatopatias/etiologia , Macrófagos/imunologia , Monócitos/imunologia , Monócitos/patologia , Tripanossomíase Africana/imunologia , Animais , Apoptose , Western Blotting , Proliferação de Células , Feminino , Citometria de Fluxo , Técnicas Imunoenzimáticas , Inflamação/patologia , Interleucina-10/genética , Interleucina-10/metabolismo , Hepatopatias/patologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/imunologia , Células Mieloides/patologia , Fagocitose , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Trypanosoma congolense/imunologia , Tripanossomíase Africana/complicações , Tripanossomíase Africana/parasitologia , Células Tumorais CultivadasRESUMO
Pancreas injury by partial duct ligation (PDL) activates a healing response, encompassing ß-cell neogenesis and proliferation. Macrophages (MΦs) were recently shown to promote ß-cell proliferation after PDL, but they remain poorly characterized. We assessed myeloid cell diversity and the factors driving myeloid cell dynamics following acute pancreas injury by PDL. In naive and sham-operated pancreas, the myeloid cell compartment consisted mainly of two distinct tissue-resident MΦ types, designated MHC-II(lo) and MHC-II(hi) MΦs, the latter being predominant. MHC-II(lo) and MHC-II(hi) pancreas MΦs differed at the molecular level, with MHC-II(lo) MΦs being more M2-activated. After PDL, there was an early surge of Ly6C(hi) monocyte infiltration in the pancreas, followed by a transient MHC-II(lo) MΦ peak and ultimately a restoration of the MHC-II(hi) MΦ-dominated steady-state equilibrium. These intricate MΦ dynamics in PDL pancreas depended on monocyte recruitment by C-C chemokine receptor 2 and macrophage-colony stimulating factor receptor as well as on macrophage-colony stimulating factor receptor-dependent local MΦ proliferation. Functionally, MHC-II(lo) MΦs were more angiogenic. We further demonstrated that, at least in C-C chemokine receptor 2-KO mice, tissue MΦs, rather than Ly6C(hi) monocyte-derived MΦs, contributed to ß-cell proliferation. Together, our study fully characterizes the MΦ subsets in the pancreas and clarifies the complex dynamics of MΦs after PDL injury.
Assuntos
Macrófagos/imunologia , Macrófagos/patologia , Monócitos/imunologia , Monócitos/patologia , Pâncreas/imunologia , Pâncreas/lesões , Animais , Antígenos Ly/metabolismo , Movimento Celular/imunologia , Proliferação de Células , Microambiente Celular/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Ligadura , Ativação de Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células Mieloides/classificação , Células Mieloides/imunologia , Células Mieloides/patologia , Pâncreas/patologia , Ductos Pancreáticos/lesões , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Regeneração/imunologiaRESUMO
The tumor stroma has long been ignored as therapeutic target, but it has become clear that several stromal cell types play a nonredundant role during tumor progression. In particular, macrophages possess the capacity to stimulate tumor growth and metastasis via multiple mechanisms. In this issue of the European Journal of Immunology, a study by Tymoszuk et al. Eur. J. Immunol. 2014. 44: 2247-2262 demonstrates that both monocyte recruitment and local macrophage proliferation determines the tumor-associated macrophage (TAM) pool size in HER2/Neu-driven mammary carcinomas. These tumors contain two main TAM subsets--MHC class II (MHC-II)(lo) F4/80(hi) and MHC-II(hi) F4/80(lo)--similar to what was observed in other tumor models. Interestingly, only the MHC-II(lo) F4/80(hi) subset is largely absent in a STAT1-deficient background. STAT1 induces the expression of CSF-1, which in turn drives TAM proliferation and possibly also the M2 gene signature of MHC-II(lo) F4/80(hi) TAM. Conversely, STAT1 deficiency upregulates M2 gene expression in MHC-II(hi) F4/80(lo) TAM, demonstrating that both TAM subsets are differentially regulated, probably as a consequence of their distinct intratumoral localization. In this Commentary, we place these findings in the context of current knowledge and propose new avenues for future research.
Assuntos
Macrófagos/imunologia , Macrófagos/metabolismo , Fator de Transcrição STAT1/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Proliferação de Células , Feminino , Genes MHC da Classe II/imunologia , Humanos , Fator Estimulador de Colônias de Macrófagos/imunologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Receptor ErbB-2/metabolismo , Fator de Transcrição STAT1/imunologiaRESUMO
Chemotherapy has been a standard treatment for cancer for the past several decades and has long been suspected to cause systemic immune suppression. However, in recent years it has become clear that the immune status of a patient is an independent prognostic factor for chemotherapeutic efficacy, and that T-cell-mediated responses actively contribute to the tumor destruction triggered by some chemotherapeutic agents. In this respect, the induction of immunogenic cell death by these compounds appears to be crucial. In this issue of the European Journal of Immunology, a study by Hannesdóttir et al. [Eur. J. Immunol. 2013. 43: 2718-2729] demonstrates a crucial role for the IFN signaling molecule STAT1 during doxorubicin and Lapatinib treatment of HER2/Neu-driven mammary carcinomas. The genotoxic anthracycline doxorubicin causes immunogenic cancer cell death and is expected to depend on the immune system, but the dual ErbB2/HER2/Neu and ErbB1/EGFR inhibitor Lapatinib also turns out to cause immune reactivity. Although CD8⺠T cells are partially involved in this phenomenon, doxorubicin, and Lapatinib also affect the myeloid infiltrate (i.e. tumor-associated macrophages and monocytes) in tumors. In this Commentary, we place these findings in the context of current knowledge and propose new avenues for future research.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Quinazolinas/administração & dosagem , Fator de Transcrição STAT1/metabolismo , Animais , Feminino , Humanos , LapatinibRESUMO
BACKGROUND: Modulation and depletion strategies of regulatory T cells (Tregs) constitute valid approaches in antitumor immunotherapy but suffer from severe adverse effects due to their lack of selectivity for the tumor-infiltrating (ti-)Treg population, indicating the need for a ti-Treg specific biomarker. METHODS: We employed single-cell RNA-sequencing in a mouse model of non-small cell lung carcinoma (NSCLC) to obtain a comprehensive overview of the tumor-infiltrating T-cell compartment, with a focus on ti-Treg subpopulations. These findings were validated by flow cytometric analysis of both mouse (LLC-OVA, MC38 and B16-OVA) and human (NSCLC and melanoma) tumor samples. We generated two CCR8-specific nanobodies (Nbs) that recognize distinct epitopes on the CCR8 extracellular domain. These Nbs were formulated as tetravalent Nb-Fc fusion proteins for optimal CCR8 binding and blocking, containing either an antibody-dependent cell-mediated cytotoxicity (ADCC)-deficient or an ADCC-prone Fc region. The therapeutic use of these Nb-Fc fusion proteins was evaluated, either as monotherapy or as combination therapy with anti-programmed cell death protein-1 (anti-PD-1), in both the LLC-OVA and MC38 mouse models. RESULTS: We were able to discern two ti-Treg populations, one of which is characterized by the unique expression of Ccr8 in conjunction with Treg activation markers. Ccr8 is also expressed by dysfunctional CD4+ and CD8+ T cells, but the CCR8 protein was only prominent on the highly activated and strongly T-cell suppressive ti-Treg subpopulation of mouse and human tumors, with no major CCR8-positivity found on peripheral Tregs. CCR8 expression resulted from TCR-mediated Treg triggering in an NF-κB-dependent fashion, but was not essential for the recruitment, activation nor suppressive capacity of these cells. While treatment of tumor-bearing mice with a blocking ADCC-deficient Nb-Fc did not influence tumor growth, ADCC-prone Nb-Fc elicited antitumor immunity and reduced tumor growth in synergy with anti-PD-1 therapy. Importantly, ADCC-prone Nb-Fc specifically depleted ti-Tregs in a natural killer (NK) cell-dependent fashion without affecting peripheral Tregs. CONCLUSIONS: Collectively, our findings highlight the efficacy and safety of targeting CCR8 for the depletion of tumor-promoting ti-Tregs in combination with anti-PD-1 therapy.
Assuntos
Antineoplásicos Imunológicos/farmacologia , Carcinoma Pulmonar de Lewis/terapia , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Depleção Linfocítica , Linfócitos do Interstício Tumoral/imunologia , Melanoma Experimental/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores CCR8/deficiência , Neoplasias Cutâneas/terapia , Linfócitos T Reguladores/imunologia , Animais , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/metabolismo , Terapia Combinada , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terapia de Alvo Molecular , Fenótipo , Receptor de Morte Celular Programada 1/metabolismo , RNA-Seq , Receptores CCR8/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Linfócitos T Reguladores/metabolismoRESUMO
Inflammatory Ly6Chi monocytes can give rise to distinct mononuclear myeloid cells in the tumor microenvironment, such as monocytic myeloid-derived suppressor cells (Mo-MDSC), immature macrophages, M2-like tumor-associated macrophages (TAMs), M1-like TAMs or monocyte-derived dendritic cells (Mo-DCs). This protocol describes a method to assess the fate and recruitment of inflammatory Ly6Chi monocytes in the tumor microenvironment.
RESUMO
Vaccinia-H1 Related (VHR) dual-specificity phosphatase, or DUSP3, plays an important role in cell cycle regulation and its expression is altered in several human cancers. In mouse model, DUSP3 deletion prevents neo-angiogenesis and b-FGF-induced microvessel outgrowth. Considering the importance of angiogenesis in metastasis formation, our study aimed to investigate the role of DUSP3 in tumour cell dissemination. Using a Lewis Lung carcinoma (LLC) experimental metastasis model, we observed that DUSP3-/- mice developed larger lung metastases than littermate controls. DUSP3-/- bone marrow transfer to lethally irradiated DUSP3+/+ mice was sufficient to transfer the phenotype to DUSP3+/+ mice, indicating that hematopoietic cells compartment was involved in the increased tumour cell dissemination to lung tissues. Interestingly, we found a higher percentage of tumour-promoting Ly6Cint macrophages in DUSP3-/- LLC-bearing lung homogenates that was at least partially due to a better recruitment of these cells. This was confirmed by 1) the presence of higher number of the Ly6Bhi macrophages in DUSP3-/- lung homogenates and by 2) the better migration of DUSP3-/- bone marrow sorted monocytes, peritoneal macrophages and bone marrow derived macrophages (BMDMs), compared to DUSP3+/+ monocytes, macrophages and BMDMs, in response to LLC-conditioned medium. Our study demonstrates that DUSP3 phosphatase plays a key role in metastatic growth through a mechanism involving the recruitment of macrophages towards LLC-bearing lungs.
Assuntos
Fosfatase 3 de Especificidade Dupla/metabolismo , Deleção de Genes , Neoplasias Pulmonares/secundário , Macrófagos/patologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Neoplasias Pulmonares/patologia , Macrófagos/efeitos dos fármacos , Masculino , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Monócitos/patologiaRESUMO
Tumors contain a heterogeneous myeloid fraction comprised of discrete MHC-II(hi) and MHC-II(lo) tumor-associated macrophage (TAM) subpopulations that originate from Ly6C(hi) monocytes. However, the mechanisms regulating the abundance and phenotype of distinct TAM subsets remain unknown. Here, we investigated the role of macrophage colony-stimulating factor (M-CSF) in TAM differentiation and polarization in different mouse tumor models. We demonstrate that treatment of tumor-bearing mice with a blocking anti-M-CSFR monoclonal antibody resulted in a reduction of mature TAMs due to impaired recruitment, extravasation, proliferation, and maturation of their Ly6C(hi) monocytic precursors. M-CSFR signaling blockade shifted the MHC-II(lo)/MHC-II(hi) TAM balance in favor of the latter as observed by the preferential differentiation of Ly6C(hi) monocytes into MHC-II(hi) TAMs. In addition, the genetic and functional signatures of MHC-II(lo) TAMs were downregulated upon M-CSFR blockade, indicating that M-CSFR signaling shapes the MHC-II(lo) TAM phenotype. Conversely, granulocyte macrophage (GM)-CSFR had no effect on the mononuclear tumor infiltrate or relative abundance of TAM subsets. However, GM-CSFR signaling played an important role in fine-tuning the MHC-II(hi) phenotype. Overall, our data uncover the multifaceted and opposing roles of M-CSFR and GM-CSFR signaling in governing the phenotype of macrophage subsets in tumors, and provide new insight into the mechanism of action underlying M-CSFR blockade.
Assuntos
Macrófagos/metabolismo , Monócitos/metabolismo , Receptores de Fator Estimulador de Colônias/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Microambiente Tumoral/fisiologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Diferenciação Celular/fisiologia , Polaridade Celular/fisiologia , Feminino , Fator Estimulador de Colônias de Macrófagos/imunologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/patologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/patologia , Receptores de Fator Estimulador de Colônias/antagonistas & inibidores , Receptores de Fator Estimulador de Colônias/imunologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Transdução de SinaisRESUMO
Various steady state and inflamed tissues have been shown to contain a heterogeneous DC population consisting of developmentally distinct subsets, including cDC1s, cDC2s and monocyte-derived DCs, displaying differential functional specializations. The identification of functionally distinct tumour-associated DC (TADC) subpopulations could prove essential for the understanding of basic TADC biology and for envisaging targeted immunotherapies. We demonstrate that multiple mouse tumours as well as human tumours harbour ontogenically discrete TADC subsets. Monocyte-derived TADCs are prominent in tumour antigen uptake, but lack strong T-cell stimulatory capacity due to NO-mediated immunosuppression. Pre-cDC-derived TADCs have lymph node migratory potential, whereby cDC1s efficiently activate CD8+ T cells and cDC2s induce Th17 cells. Mice vaccinated with cDC2s displayed a reduced tumour growth accompanied by a reprogramming of pro-tumoural TAMs and a reduction of MDSCs, while cDC1 vaccination strongly induces anti-tumour CTLs. Our data might prove important for therapeutic interventions targeted at specific TADC subsets or their precursors.
Assuntos
Células Dendríticas/imunologia , Neoplasias/imunologia , Microambiente Tumoral/imunologia , Animais , Linhagem Celular Tumoral , Células Cultivadas , Humanos , Imunoterapia/métodos , Macrófagos/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Monócitos/imunologia , Neoplasias/patologia , Neoplasias/terapia , Subpopulações de Linfócitos T/imunologiaRESUMO
Neoadjuvant radiotherapy (neoRT) used in cancer treatments aims at improving local tumor control and patient overall survival. The neoRT schedule and the timing of the surgical treatment (ST) are empirically based and influenced by the clinician's experience. The current study examines how the sequencing of neoRT and ST affects metastatic dissemination. In a breast carcinoma model, tumors were exposed to different neoRT schedules (2x5Gy or 5x2Gy) followed by surgery at day 4 or 11 post-RT. The impact on the tumor microenvironment and lung metastases was evaluated through immunohistochemical and flow cytometry analyses. After 2x5Gy, early ST (at day 4 post-RT) led to increased size and number of lung metastases as compared to ST performed at day 11. Inversely, after 5x2Gy neoRT, early ST protected the mice against lung metastases. This intriguing relationship between tumor aggressiveness and ST timing could not be explained by differences in classical parameters studied such as hypoxia, vessel density and matrix remodeling. The study of tumor-related inflammation and immunity reveals an increased circulating NK cell percentage following neoRT as compared to non irradiated mice. Then, radiation treatment and surgery were applied to tumor-bearing NOD/SCID mice. In the absence of NK cells, neoRT appears to increase lung metastatic dissemination as compared to non irradiated tumor-bearing mice. Altogether our data demonstrate that the neoRT schedule and the ST timing affect metastasis formation in a pre-clinical model and points out the potential role of NK cells. These findings highlight the importance to cautiously tailor the optimal window for ST following RT.
Assuntos
Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Camundongos , Camundongos SCID , Terapia Neoadjuvante , Metástase Neoplásica , Radioterapia Adjuvante , Fatores de Tempo , Microambiente Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Identifying pathways for ß-cell generation is essential for cell therapy in diabetes. We investigated the potential of 17ß-estradiol (E2) and estrogen receptor (ER) signaling for stimulating ß-cell generation during embryonic development and in the severely injured adult pancreas. E2 concentration, ER activity, and number of ERα transcripts were enhanced in the pancreas injured by partial duct ligation (PDL) along with nuclear localization of ERα in ß-cells. PDL-induced proliferation of ß-cells depended on aromatase activity. The activation of Neurogenin3 (Ngn3) gene expression and ß-cell growth in PDL pancreas were impaired when ERα was turned off chemically or genetically (ERα(-/-)), whereas in situ delivery of E2 promoted ß-cell formation. In the embryonic pancreas, ß-cell replication, number of Ngn3(+) progenitor cells, and expression of key transcription factors of the endocrine lineage were decreased by ERα inactivation. The current study reveals that E2 and ERα signaling can drive ß-cell replication and formation in mouse pancreas.
Assuntos
Proliferação de Células/genética , Estradiol/metabolismo , Receptor alfa de Estrogênio/genética , Regulação da Expressão Gênica no Desenvolvimento , Células Secretoras de Insulina/metabolismo , Pâncreas/embriologia , Ductos Pancreáticos/lesões , RNA Mensageiro/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Núcleo Celular/metabolismo , Receptor alfa de Estrogênio/metabolismo , Células Secretoras de Insulina/citologia , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Pâncreas/citologiaRESUMO
UNLABELLED: Macrophages are classically considered detrimental for pancreatic ß-cell survival and function, thereby contributing to ß-cell failure in both type 1 (T1D) and 2 (T2D) diabetes mellitus. In addition, adipose tissue macrophages negatively influence peripheral insulin signaling and promote obesity-induced insulin resistance in T2D. In contrast, recent data unexpectedly uncovered that macrophages are not only able to protect ß cells during pancreatitis but also to orchestrate ß-cell proliferation and regeneration after ß-cell injury. Moreover, by altering their activation state, macrophages are able to improve insulin resistance in murine models of T2D. This review will elaborate on current insights in macrophage heterogeneity and on the evolving role of pancreas macrophages during organogenesis, tissue injury, and repair. Additional identification of macrophage subtypes and of their secreted factors might ultimately translate into novel therapeutic strategies for both T1D and T2D. SIGNIFICANCE: Diabetes mellitus is a pandemic disease, characterized by severe acute and chronic complications. Macrophages have long been considered prime suspects in the pathogenesis of both type 1 and 2 diabetes mellitus. In this concise review, current insights in macrophage heterogeneity and on the, as yet, underappreciated role of alternatively activated macrophages in insulin sensing and ß-cell development/repair are reported. Further identification of macrophage subtypes and of their secreted factors might ultimately translate into novel therapeutic strategies for diabetes mellitus.
Assuntos
Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Macrófagos/metabolismo , Regeneração , Animais , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/terapia , Humanos , Macrófagos/patologia , Pancreatite/metabolismo , Pancreatite/patologia , Pancreatite/terapiaRESUMO
Tumor-associated macrophages (TAMs) provide a significant contribution to tumor growth and metastasis. We demonstrated the existence of two main TAM subsets, differing in activation state and localization. Of these, M2-like TAMs reside in hypoxic regions of the tumor mass and can be used as targets for hypoxia tracers. This said, hypoxia does not regulate the differentiation of TAMs but finely tunes the activity of the M2-like population.
RESUMO
The survival of breast cancer patients with metastatic disease has not markedly improved over recent decades, highlighting the need to better understand this process. In this issue of Science Signaling, Pignatelli et al. used freshly obtained invasive ductal carcinoma cells from patients to demonstrate the need for high abundance of the invasive isoform of the Mena protein (Mena(INV)) in cancer cells and colony-stimulating factor 1 (CSF-1)-mediated paracrine signaling in macrophages for efficient transendothelial migration and metastasis formation in all clinical breast cancer subtypes. Furthermore, the triple negative and HER2(+) subtypes, but not the ERPR(+)/HER2(-) subtype, had high CSF-1 receptor (CSF-1R) abundance and also partially used autocrine CSF-1/CSF-1R signaling for invasion. These data establish Mena(INV), CSF-1/CSF-1R, and macrophages as potential therapeutic targets for most human breast cancers.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Macrófagos/fisiologia , Proteínas dos Microfilamentos/análise , Invasividade Neoplásica/fisiopatologia , Proteínas de Neoplasias/análise , Migração Transendotelial e Transepitelial/fisiologia , Animais , Feminino , HumanosRESUMO
The current review article describes the functional relationship between tumor-associated macrophages (TAM) as key cellular contributors to cancer malignancy on the one hand and macrophage-colony-stimulating factor (M-CSF or CSF-1) as an important molecular contributor on the other. We recapitulate the available data on expression of M-CSF and the M-CSF receptor (M-CSFR) in human tumor tissue as constituents of a stromal macrophage signature and on the limits of the predictive and prognostic value of plasma M-CSF levels. After providing an update on current insights into the nature of TAM heterogeneity at the level of M1/M2 phenotype and TAM subsets, we give an overview of experimental evidence, based on genetic, antibody-mediated, and pharmacological disruption of M-CSF/M-CSFR signaling, for the extent to which M-CSFR signaling can not only determine the TAM quantity, but can also contribute to shaping the phenotype and heterogeneity of TAM and other related tumor-infiltrating myeloid cells (TIM). Finally, we review the accumulating information on the - sometimes conflicting - effects blocking M-CSFR signaling may have on various aspects of cancer progression such as tumor growth, invasion, angiogenesis, metastasis, and resistance to therapy and we thereby discuss in how far these different effects actually reflect a contribution of TAM.
RESUMO
Macrophages are extremely versatile cells that adopt a distinct phenotype in response to a changing microenvironment. Consequently, macrophages are involved in diverse functions, ranging from organogenesis and tissue homeostasis to recognition and destruction of invading pathogens. In cancer, tumor-associated macrophages (TAM) often contribute to tumor progression by increasing cancer cell migration and invasiveness, stimulating angiogenesis, and suppressing anti-tumor immunity. Accumulating evidence suggests that these different functions could be exerted by specialized TAM subpopulations. Here, we discuss the potential underlying mechanisms regulating TAM specialization and elaborate on TAM heterogeneity in terms of their ontogeny, activation state, and intra-tumoral localization. In addition, parallels are drawn between TAM and macrophages in other tissues. Together, a better understanding of TAM diversity could provide a rationale for novel strategies aimed at targeting the most potent tumor-supporting macrophages.
RESUMO
Tumor-associated macrophages (TAM) are exposed to multiple microenvironmental cues in tumors, which collaborate to endow these cells with protumoral activities. Hypoxia, caused by an imbalance in oxygen supply and demand because of a poorly organized vasculature, is often a prominent feature in solid tumors. However, to what extent tumor hypoxia regulates the TAM phenotype in vivo is unknown. Here, we show that the myeloid infiltrate in mouse lung carcinoma tumors encompasses two morphologically distinct CD11b(hi)F4/80(hi)Ly6C(lo) TAM subsets, designated as MHC-II(lo) and MHC-II(hi) TAM, both of which were derived from tumor-infiltrating Ly6C(hi) monocytes. MHC-II(lo) TAM express higher levels of prototypical M2 markers and reside in more hypoxic regions. Consequently, MHC-II(lo) TAM contain higher mRNA levels for hypoxia-regulated genes than their MHC-II(hi) counterparts. To assess the in vivo role of hypoxia on these TAM features, cancer cells were inoculated in prolyl hydroxylase domain 2 (PHD2)-haplodeficient mice, resulting in better-oxygenated tumors. Interestingly, reduced tumor hypoxia did not alter the relative abundance of TAM subsets nor their M2 marker expression, but specifically lowered hypoxia-sensitive gene expression and angiogenic activity in the MHC-II(lo) TAM subset. The same observation in PHD2(+/+) â PHD2(+/-) bone marrow chimeras also suggests organization of a better-oxygenized microenvironment. Together, our results show that hypoxia is not a major driver of TAM subset differentiation, but rather specifically fine-tunes the phenotype of M2-like MHC-II(lo) TAM.
Assuntos
Hipóxia Celular/fisiologia , Macrófagos/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Animais , Diferenciação Celular/fisiologia , Modelos Animais de Doenças , Feminino , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias/genética , TranscriptomaRESUMO
Myeloid-derived suppressor cells are immature myeloid cells, consisting of a monocytic and a granulocytic fraction, that are known to suppress anti-tumor immune responses. Important targets of the immunosuppressive capacity of MDSC are CD8(+) T cells, which are crucial cytotoxic effector cells in immunotherapeutic settings. CD8(+) T-cell activation and differentiation comprises a well-orchestrated series of events, starting from early TCR-mediated signaling and leading to cytokine secretion, the expression of activation markers, proliferation and the differentiation into several subsets of effector and memory cells. In this review, we summarize the available data on how the production of reactive oxygen species, nitric oxide, the arginase-mediated depletion of l-arginine and Cystine depletion by MDSCs interfere with the signaling molecules necessary for normal CTL differentiation and activation.