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1.
Cell ; 178(2): 346-360.e24, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31257026

RESUMO

Neutrophils are a component of the tumor microenvironment and have been predominantly associated with cancer progression. Using a genetic approach complemented by adoptive transfer, we found that neutrophils are essential for resistance against primary 3-methylcholantrene-induced carcinogenesis. Neutrophils were essential for the activation of an interferon-γ-dependent pathway of immune resistance, associated with polarization of a subset of CD4- CD8- unconventional αß T cells (UTCαß). Bulk and single-cell RNA sequencing (scRNA-seq) analyses unveiled the innate-like features and diversity of UTCαß associated with neutrophil-dependent anti-sarcoma immunity. In selected human tumors, including undifferentiated pleomorphic sarcoma, CSF3R expression, a neutrophil signature and neutrophil infiltration were associated with a type 1 immune response and better clinical outcome. Thus, neutrophils driving UTCαß polarization and type 1 immunity are essential for resistance against murine sarcomas and selected human tumors.


Assuntos
Resistência à Doença , Neoplasias/patologia , Neutrófilos/imunologia , Sarcoma/patologia , Linfócitos T/metabolismo , Animais , Cromonas/toxicidade , Resistência à Doença/imunologia , Humanos , Imunidade Inata , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Estimativa de Kaplan-Meier , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/imunologia , Neoplasias/mortalidade , Infiltração de Neutrófilos , Neutrófilos/citologia , Neutrófilos/metabolismo , Receptores de Fator Estimulador de Colônias/metabolismo , Sarcoma/induzido quimicamente , Sarcoma/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Microambiente Tumoral
2.
Nat Immunol ; 22(5): 595-606, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33903766

RESUMO

Although the pathological significance of tumor-associated macrophage (TAM) heterogeneity is still poorly understood, TAM reprogramming is viewed as a promising anticancer therapy. Here we show that a distinct subset of TAMs (F4/80hiCD115hiC3aRhiCD88hi), endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1), plays a critical role in shaping a prometastatic tumor microenvironment favoring immunosuppression, angiogenesis and epithelial-to-mesenchymal transition. This population originates from F4/80+HO-1+ bone marrow (BM) precursors, accumulates in the blood of tumor bearers and preferentially localizes at the invasive margin through a mechanism dependent on the activation of Nrf2 and coordinated by the NF-κB1-CSF1R-C3aR axis. Inhibition of F4/80+HO-1+ TAM recruitment or myeloid-specific deletion of HO-1 blocks metastasis formation and improves anticancer immunotherapy. Relative expression of HO-1 in peripheral monocyte subsets, as well as in tumor lesions, discriminates survival among metastatic melanoma patients. Overall, these results identify a distinct cancer-induced HO-1+ myeloid subgroup as a new antimetastatic target and prognostic blood marker.


Assuntos
Biomarcadores Tumorais/metabolismo , Heme Oxigenase-1/metabolismo , Neoplasias Pulmonares/imunologia , Melanoma/imunologia , Neoplasias Cutâneas/imunologia , Macrófagos Associados a Tumor/imunologia , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/sangue , Linhagem Celular Tumoral/transplante , Quimioterapia Adjuvante/métodos , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/imunologia , Feminino , Heme/metabolismo , Heme Oxigenase-1/antagonistas & inibidores , Heme Oxigenase-1/sangue , Heme Oxigenase-1/genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Masculino , Melanoma/mortalidade , Melanoma/secundário , Melanoma/terapia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Células Progenitoras Mieloides/imunologia , Células Progenitoras Mieloides/metabolismo , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/metabolismo
3.
Cell ; 160(4): 700-714, 2015 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-25679762

RESUMO

PTX3 is an essential component of the humoral arm of innate immunity, playing a nonredundant role in resistance against selected microbes and in the regulation of inflammation. PTX3 activates and regulates the Complement cascade by interacting with C1q and with Factor H. PTX3 deficiency was associated with increased susceptibility to mesenchymal and epithelial carcinogenesis. Increased susceptibility of Ptx3(-/-) mice was associated with enhanced macrophage infiltration, cytokine production, angiogenesis, and Trp53 mutations. Correlative evidence, gene-targeted mice, and pharmacological blocking experiments indicated that PTX3 deficiency resulted in amplification of Complement activation, CCL2 production, and tumor-promoting macrophage recruitment. PTX3 expression was epigenetically regulated in selected human tumors (e.g., leiomyosarcomas and colorectal cancer) by methylation of the promoter region and of a putative enhancer. Thus, PTX3, an effector molecule belonging to the humoral arm of innate immunity, acts as an extrinsic oncosuppressor gene in mouse and man by regulating Complement-dependent, macrophage-sustained, tumor-promoting inflammation.


Assuntos
Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Inflamação/metabolismo , Neoplasias/imunologia , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/metabolismo , Animais , Proteínas do Sistema Complemento/metabolismo , Metilação de DNA , Genes p53 , Humanos , Camundongos , Mutação
4.
Cancer Immunol Immunother ; 73(11): 228, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39249578

RESUMO

BACKGROUND: The antigen processing machinery (APM) plays a critical role in generating tumor-specific antigens that can be recognized and targeted by the immune system. Proper functioning of APM components is essential for presenting these antigens on the surface of tumor cells, enabling immune detection and destruction. In many cancers, defects in APM can lead to immune evasion, contributing to tumor progression and poor clinical outcomes. However, the status of the APM in sarcomas is not well characterized, limiting the development of effective immunotherapeutic strategies for these patients. METHODS: We investigated 126 patients with 8 types of bone and soft tissue sarcoma operated between 2001-2021. Tissue microarrays mapped 11 specific areas in each case. The presence/absence of APM protein was determined through immunohistochemistry. Bayesian networks were used. RESULTS: All investigated sarcomas had some defects in APM. The least damaged component was HLA Class I subunit ß2-microglobulin and HLA Class II. The proteasome LMP10 subunit was defective in leiomyosarcoma (LMS), myxoid liposarcoma (MLPS), and dedifferentiated liposarcoma (DDLPS), while MHC I transporting unit TAP2 was altered in undifferentiated pleomorphic sarcoma (UPS), gastrointestinal stromal tumor (GIST), and chordoma (CH). Among different neoplastic areas, high-grade areas showed different patterns of expression compared to high lymphocytic infiltrate areas. Heterogeneity at the patient level was also observed. Loss of any APM component was prognostic of distant metastasis (DM) for LMS and DDLPS and of overall survival (OS) for LMS. CONCLUSION: Sarcomas exhibit a high degree of defects in APM components, with differences among histotypes and tumoral areas. The most commonly altered APM components were HLA Class I subunit ß2-microglobulin, HLA Class I subunit α (HC10), and MHC I transporting unit TAP2. The loss of APM components was prognostic of DM and OS and clinically relevant for LMS and DDLPS. This study explores sarcoma molecular mechanisms, enriching personalized therapeutic approaches.


Assuntos
Apresentação de Antígeno , Sarcoma , Humanos , Sarcoma/imunologia , Sarcoma/patologia , Apresentação de Antígeno/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Microglobulina beta-2/metabolismo , Prognóstico , Membro 3 da Subfamília B de Transportadores de Cassetes de Ligação de ATP
5.
Br J Haematol ; 193(6): 1157-1171, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33713428

RESUMO

B-cell acute lymphoblastic leukaemia (B-ALL) reprograms the surrounding bone marrow (BM) stroma to create a leukaemia-supportive niche. To elucidate the contribution of immune cells to the leukaemic microenvironment, we investigated the involvement of monocyte/macrophage compartments, as well as several recruitment pathways in B-ALL development. Immunohistochemistry analyses showed that CD68-expressing macrophages were increased in leukaemic BM biopsies, compared to controls and predominantly expressed the M2-like markers CD163 and CD206. Furthermore, the "non-classical" CD14+ CD16++ monocyte subset, expressing high CX3CR1 levels, was significantly increased in B-ALL patients' peripheral blood. CX3CL1 was shown to be significantly upregulated in leukaemic BM plasma, thus providing an altered migratory pathway possibly guiding NC monocyte recruitment into the BM. Additionally, the monocyte/macrophage chemoattractant chemokine ligand 2 (CCL2) strongly increased in leukaemic BM plasma, possibly because of the interaction of leukaemic cells with mesenchymal stromal cells and vascular cells and due to a stimulatory effect of leukaemia-related inflammatory mediators. C5a, a macrophage chemoattractant and M2-polarizing factor, further appeared to be upregulated in the leukaemic BM, possibly as an effect of PTX3 decrease, that could unleash complement cascade activation. Overall, deregulated monocyte/macrophage compartments are part of the extensive BM microenvironment remodelling at B-ALL diagnosis and could represent valuable targets for novel treatments to be coupled with classical chemotherapy.


Assuntos
Antígenos CD/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Proteínas de Neoplasias/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Microambiente Tumoral , Adolescente , Adulto , Idoso , Técnicas de Cocultura , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia
6.
Am J Physiol Lung Cell Mol Physiol ; 314(6): L1010-L1025, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29469612

RESUMO

Chemokines coordinate lung inflammation and fibrosis by acting on chemokine receptors expressed on leukocytes and other cell types. Atypical chemokine receptors (ACKRs) bind, internalize, and degrade chemokines, tuning homeostasis and immune responses. ACKR2 recognizes and decreases the levels of inflammatory CC chemokines. The role of ACKR2 in fibrogenesis is unknown. The purpose of the study was to investigate the role of ACKR2 in the context of pulmonary fibrosis. The effects of ACKR2 expression and deficiency during inflammation and fibrosis were analyzed using a bleomycin-model of fibrosis, ACKR2-deficient mice, bone marrow chimeras, and antibody-mediated leukocyte depletion. ACKR2 was upregulated acutely in response to bleomycin and normalized over time. ACKR2-/- mice showed reduced lethality and lung fibrosis. Bone marrow chimeras showed that lethality and fibrosis depended on ACKR2 expression in pulmonary resident (nonhematopoietic) cells but not on leukocytes. ACKR2-/- mice exhibited decreased expression of tissue-remodeling genes, reduced leukocyte influx, pulmonary injury, and dysfunction. ACKR2-/- mice had early increased levels of CCL5, CCL12, CCL17, and IFNγ and an increased number of CCR2+ and CCR5+ IFNγ-producing γδT cells in the airways counterbalanced by low Th17-lymphocyte influx. There was reduced accumulation of IFNγ-producing γδT cells in CCR2-/- and CCR5-/- mice. Moreover, depletion of γδT cells worsened the clinical symptoms induced by bleomycin and reversed the phenotype of ACKR2-/- mice exposed to bleomycin. ACKR2 controls the CC chemokine expression that drives the influx of CCR2+ and CCR5+ IFNγ-producing γδT cells, tuning the Th17 response that mediated pulmonary fibrosis triggered by bleomycin instillation.


Assuntos
Interferon gama/imunologia , Fibrose Pulmonar/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores CCR2/imunologia , Receptores CCR5/imunologia , Células Th17/imunologia , Animais , Bleomicina/efeitos adversos , Bleomicina/farmacologia , Quimiocinas/genética , Quimiocinas/imunologia , Interferon gama/genética , Camundongos , Camundongos Knockout , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores CCR2/genética , Receptores CCR5/genética , Células Th17/patologia
7.
J Infect Dis ; 208(1): 130-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23087427

RESUMO

BACKGROUND: In cystic fibrosis (CF) patients, chronic lung infection and inflammation due to Pseudomonas aeruginosa contribute to the decline of lung function. The increased prevalence of multidrug resistance among bacteria and the adverse effects of antiinflammatory agents highlight the need for alternative therapeutic approaches that should be tested in a relevant animal model. METHODS: Gut-corrected CF and non-CF mice were chronically infected with a multidrug-resistant P. aeruginosa strain and treated with the long pentraxin PTX3. Body weight, bacterial count, inflammation, and lung pathology were evaluated after 12 days. PTX3 localization in CF sputum specimens was analyzed by immunofluorescence. RESULTS: Chronic P. aeruginosa infection developed similarly in CF and non-CF mice but differed in terms of the inflammatory response. Leukocyte recruitment in the airways, cytokine levels, and chemokine levels were significantly higher in CF mice, compared with non-CF mice. PTX3 treatment, which facilitates phagocytosis of pathogens, reduced P. aeruginosa colonization and restored airway inflammation in CF mice to levels observed in non-CF mice. The presence of PTX3 in CF sputum, in leukocytes, or bound to P. aeruginosa macrocolonies, as well as previous data on PTX3 polymorphisms in colonized CF patients, confirm the relevance of this molecule. CONCLUSIONS: These findings represent a step forward in demonstrating the therapeutic potential of PTX3 in CF.


Assuntos
Proteína C-Reativa/uso terapêutico , Camundongos Endogâmicos CFTR/microbiologia , Infecções por Pseudomonas/imunologia , Componente Amiloide P Sérico/uso terapêutico , Animais , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos CFTR/imunologia , Fagocitose/imunologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/patologia , Proteínas Recombinantes/uso terapêutico
8.
Discov Med ; 36(182): 632-645, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38531804

RESUMO

BACKGROUND: Ovarian cancer (OC) accounts for about 4% of female cancers globally. While Ki67-immunopositive (Ki67+) cell density is commonly used to assess proliferation in OC, the two-dimensional (2D) distribution pattern of these cells is poorly understood. This study explores the 2D distribution pattern of Ki67+ cells in primary OC tissues and models the proliferation process to improve our understanding of this hallmark of cancer. METHODS: A total of 100 tissue cores, included in a tissue microarray (TMA) representing 5 clear cell carcinomas, 62 serous carcinomas, 10 mucinous adenocarcinomas, 3 endometrioid adenocarcinomas, 10 lymph node metastases from OC, and 10 samples of adjacent normal ovary tissue, were stained using a standardized immunohistochemical protocol. The computer-aided image analysis system assessed the 2D distribution pattern of Ki67+ proliferating cells, providing the cell number and density, patterns of randomness, and cell-to-cell closeness. Three computer models were created to simulate behavior and responses, aiming to gain insights into the variations in the proliferation process. RESULTS: Significant differences in Ki67+ cell density were found between low- and high-grade serous carcinoma/mucinous adenocarcinomas (p = 0.003 and p = 0.01, respectively). The Nearest Neighbor Index of Ki67+ cells differed significantly between high-grade serous carcinomas and endometrioid adenocarcinomas (p = 0.01), indicating distinct 2D Ki67+ distribution patterns. Proxemics analysis revealed significant differences in Ki67+ cell-to-cell closeness between low- and high-grade serous carcinomas (p = 0.002). Computer models showed varied effects on the overall organization of Ki67+ cells and the ability to preserve the original 2D distribution pattern when altering the location and/or density of Ki67+ cells. CONCLUSIONS: Cell proliferation is a hallmark of OCs. This study provides new evidence that investigating the Ki67+ cell density and 2D distribution pattern can assist in understanding the proliferation status of OCs. Moreover, our computer models suggest that changes in Ki67+ cell density and their location are critical for maintaining the 2D distribution pattern.


Assuntos
Adenocarcinoma Mucinoso , Carcinoma Endometrioide , Neoplasias Ovarianas , Feminino , Humanos , Carcinoma Endometrioide/patologia , Antígeno Ki-67 , Biomarcadores Tumorais/análise , Neoplasias Ovarianas/patologia , Adenocarcinoma Mucinoso/patologia
9.
Cancer Immunol Res ; 12(4): 413-426, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38349973

RESUMO

Neutrophils are the most abundant leukocytes in human blood and play a primary role in resistance against invading microorganisms and in the acute inflammatory response. However, their role in colitis and colitis-associated colorectal cancer is still under debate. This study aims to dissect the role of neutrophils in these pathologic contexts by using a rigorous genetic approach. Neutrophil-deficient mice (Csf3r-/- mice) were used in classic models of colitis and colitis-associated colorectal cancer and the role of neutrophils was assessed by histologic, cellular, and molecular analyses coupled with adoptive cell transfer. We also performed correlative analyses using human datasets. Csf3r-/- mice showed increased susceptibility to colitis and colitis-associated colorectal cancer compared with control Csf3r+/+ mice and adoptive transfer of neutrophils in Csf3r-/- mice reverted the phenotype. In colitis, Csf3r-/- mice showed increased bacterial invasion and a reduced number of healing ulcers in the colon, indicating a compromised regenerative capacity of epithelial cells. Neutrophils were essential for γδ T-cell polarization and IL22 production. In patients with ulcerative colitis, expression of CSF3R was positively correlated with IL22 and IL23 expression. Moreover, gene signatures associated with epithelial-cell development, proliferation, and antimicrobial response were enriched in CSF3Rhigh patients. Our data support a model where neutrophils mediate protection against intestinal inflammation and colitis-associated colorectal cancer by controlling the intestinal microbiota and driving the activation of an IL22-dependent tissue repair pathway.


Assuntos
Colite Ulcerativa , Neoplasias Associadas a Colite , Neutrófilos , Animais , Humanos , Camundongos , Carcinogênese , Colite/patologia , Colite Ulcerativa/metabolismo , Neoplasias Associadas a Colite/patologia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/metabolismo
10.
Anticancer Agents Med Chem ; 23(20): 2248-2253, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36748819

RESUMO

BACKGROUND: Desmoid tumors have an extremely variable natural history. The uncertainty behind desmoid behavior reflects the complexity, which subtends its development and non-linear advancement. Apart from Wnt- ßcatenin mutation, estrogen receptors, and COX-2 overexpression, little is known about the ability of desmoids to grow and recur while being unable to metastasize. Several tumors have been shown to express the CXCR4/CXCR7/CXCL12 axis, whose functions are essential for tumoral development. AIMS: This study aimed to investigate the expression of the CXCR4/CXCR7/CXCL12 axis in primary desmoid tumors and discuss the potential role of this key-signaling as an antiangiogenic therapeutic strategy. METHODS: In this study, 3 µm-thick consecutive sections from each formalin-fixed and paraffin-embedded tissue block were treated with mouse monoclonal antibodies developed against CD34, CXCR4, CXCR7, and CXCL12. RESULTS: Two distinct vessel populations: CXCR4+ and CXCR4- vessels, have been found. Similarly, chemokine receptor CXCR7 expression in the entire desmoid tumor series positively stained a portion of tumor-associated vessels, identifying two distinct subpopulations of vessels: CXCR7+ and CXCR7- vessels. All 8 neoplastic tissue samples expressed CXCL12. Immunohistochemical positivity was identified in both stromal and endothelial vascular cells. Compared to CXCR4 and CXCR7, the vast majority of tumor-associated vessels were found to express this chemokine. CONCLUSION: It is the first time, as per our knowledge, that CXCR4/CXCR7/CXCL12 axis expression has been identified in a desmoid type-fibromatosis series. CXCL12 expression by neoplastic cells, together with CXCR4 and CXCR7 expression by a subgroup of tumor-associated vessels, was detected in all desmoid tumor tissue samples examined. Since chemokines are known contributors to neovascularization, CXCR4/CXCR7/CXCL12 axis may play a role in angiogenesis in this soft-tissue tumor histotype, thereby supporting its growth.


Assuntos
Fibromatose Agressiva , Receptores CXCR , Animais , Camundongos , Proliferação de Células , Recidiva Local de Neoplasia , Receptores CXCR/genética , Receptores CXCR/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Transdução de Sinais , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Receptores de Estrogênio
11.
Aging Cell ; 22(7): e13853, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37157887

RESUMO

Hepatic metastasis is a clinical challenge for colorectal cancer (CRC). Senescent cancer cells accumulate in CRC favoring tumor dissemination. Whether this mechanism progresses also in metastasis is unexplored. Here, we integrated spatial transcriptomics, 3D-microscopy, and multicellular transcriptomics to study the role of cellular senescence in human colorectal liver metastasis (CRLM). We discovered two distinct senescent metastatic cancer cell (SMCC) subtypes, transcriptionally located at the opposite pole of epithelial (e) to mesenchymal (m) transition. SMCCs differ in chemotherapy susceptibility, biological program, and prognostic roles. Mechanistically, epithelial (e)SMCC initiation relies on nucleolar stress, whereby c-myc dependent oncogene hyperactivation induces ribosomal RPL11 accumulation and DNA damage response. In a 2D pre-clinical model, we demonstrated that RPL11 co-localized with HDM2, a p53-specific ubiquitin ligase, leading to senescence activation in (e)SMCCs. On the contrary, mesenchymal (m)SMCCs undergo TGFß paracrine activation of NOX4-p15 effectors. SMCCs display opposing effects also in the immune regulation of neighboring cells, establishing an immunosuppressive environment or leading to an active immune workflow. Both SMCC signatures are predictive biomarkers whose unbalanced ratio determined the clinical outcome in CRLM and CRC patients. Altogether, we provide a comprehensive new understanding of the role of SMCCs in CRLM and highlight their potential as new therapeutic targets to limit CRLM progression.


Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Humanos , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Senescência Celular , Transição Epitelial-Mesenquimal
12.
Cancer Immunol Res ; 11(4): 405-420, 2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-36652202

RESUMO

Patients with colorectal liver metastasis (CLM) present with heterogenous clinical outcomes and improved classification is needed to ameliorate the therapeutic output. Macrophages (Mϕ) hold promise as prognostic classifiers and therapeutic targets. Here, stemming from a single-cell analysis of mononuclear phagocytes infiltrating human CLM, we identified two Mϕ markers associated with distinct populations with opposite clinical relevance. The invasive margin of CLM was enriched in pro-inflammatory monocyte-derived Mϕ (MoMϕ) expressing the monocytic marker SERPINB2, and a more differentiated population, tumor-associated Mϕ (TAM), expressing glycoprotein nonmetastatic melanoma protein B (GPNMB). SERPINB2+ MoMϕ had an early inflammatory profile, whereas GPNMB+ TAMs were enriched in pathways of matrix degradation, angiogenesis, and lipid metabolism and were found closer to the tumor margin, as confirmed by spatial transcriptomics on CLM specimens. In a cohort of patients, a high infiltration of SERPINB2+ cells independently associated with longer disease-free survival (DFS; P = 0.033), whereas a high density of GPNMB+ cells correlated with shorter DFS (P = 0.012) and overall survival (P = 0.002). Cell-cell interaction analysis defined opposing roles for MoMϕ and TAMs, suggesting that SERPINB2+ and GPNMB+ cells are discrete populations of Mϕ and may be exploited for further translation to an immune-based stratification tool. This study provides evidence of how multi-omics approaches can identify nonredundant, clinically relevant markers for further translation to immune-based patient stratification tools and therapeutic targets. GPNMB has been shown to set Mϕ in an immunosuppressive mode. Our high dimensional analyses provide further evidence that GPNMB is a negative prognostic indicator and a potential player in the protumor function of Mϕ populations.


Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Humanos , Prognóstico , Macrófagos/metabolismo , Monócitos/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Colorretais/metabolismo , Glicoproteínas de Membrana/metabolismo
13.
Elife ; 122023 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-37222419

RESUMO

Streptococcus pneumoniae is a major pathogen in children, elderly subjects, and immunodeficient patients. Pentraxin 3 (PTX3) is a fluid-phase pattern recognition molecule (PRM) involved in resistance to selected microbial agents and in regulation of inflammation. The present study was designed to assess the role of PTX3 in invasive pneumococcal infection. In a murine model of invasive pneumococcal infection, PTX3 was strongly induced in non-hematopoietic (particularly, endothelial) cells. The IL-1ß/MyD88 axis played a major role in regulation of the Ptx3 gene expression. Ptx3-/- mice presented more severe invasive pneumococcal infection. Although high concentrations of PTX3 had opsonic activity in vitro, no evidence of PTX3-enhanced phagocytosis was obtained in vivo. In contrast, Ptx3-deficient mice showed enhanced recruitment of neutrophils and inflammation. Using P-selectin-deficient mice, we found that protection against pneumococcus was dependent upon PTX3-mediated regulation of neutrophil inflammation. In humans, PTX3 gene polymorphisms were associated with invasive pneumococcal infections. Thus, this fluid-phase PRM plays an important role in tuning inflammation and resistance against invasive pneumococcal infection.


Assuntos
Inflamação , Infecções Pneumocócicas , Animais , Camundongos , Inflamação/metabolismo , Neutrófilos/metabolismo , Fagocitose , Infecções Pneumocócicas/genética , Infecções Pneumocócicas/metabolismo , Streptococcus pneumoniae
14.
J Autoimmun ; 38(2-3): J209-15, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22196923

RESUMO

ß2 glycoprotein I (ß2GPI)-dependent anti-phospholipid antibodies (aPL) induce thrombosis and affect pregnancy. The CMV-derived synthetic peptide TIFI mimics the PL-binding site of ß2GPI and inhibits ß2GPI cell-binding in vitro and aPL-mediated thrombosis in vivo. Here we investigated the effect of TIFI on aPL-induced fetal loss in mice. TIFI inhibitory effect on in vitro aPL binding to human trophoblasts was evaluated by indirect immunofluorescence and ELISA. TIFI effect on aPL-induced fetal loss was investigated in pregnant C57BL/6 mice treated with aPL or normal IgG (NHS). Placenta/fetus weight and histology and RNA expression were analyzed. TIFI, but not the control peptide VITT, displayed a dose-dependent inhibition of aPL binding to trophoblasts in vitro. Injection of low doses of aPL at day 0 of pregnancy caused growth retardation and increased fetal loss rate, both significantly reduced by TIFI but not VITT. Consistent with observations in humans, histological analysis showed no evidence of inflammation in this model, as confirmed by the absence of an inflammatory signature in gene expression analysis, which in turn revealed a TIFI-dependent modulation of molecules involved in differentiation and development processes. These findings support the non-inflammatory pathogenic role of aPL and suggest innovative therapeutic approaches to aPL-dependent fetal loss.


Assuntos
Aborto Espontâneo/imunologia , Anticorpos Antifosfolipídeos/imunologia , Peptídeos/metabolismo , beta 2-Glicoproteína I/química , beta 2-Glicoproteína I/metabolismo , Aborto Espontâneo/prevenção & controle , Animais , Anticorpos Antifosfolipídeos/metabolismo , Sítios de Ligação , Feminino , Perfilação da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/administração & dosagem , Peptídeos/farmacologia , Placenta/metabolismo , Placenta/patologia , Gravidez , Ligação Proteica , Trofoblastos/efeitos dos fármacos , Trofoblastos/metabolismo
15.
J Immunol ; 185(1): 642-52, 2010 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-20530259

RESUMO

Tumor-associated macrophages (TAMs) are key orchestrators of the tumor microenvironment directly affecting neoplastic cell growth, neoangiogenesis, and extracellular matrix remodeling. In turn, the tumor milieu strongly influences maturation of TAMs and shapes several of their features. To address the early macrophage (M) differentiation phase in a malignant context, we mimicked a tumor microenvironment by in vitro coculturing human blood monocytes with conditioned media from different cancer cell lines. Only 2 out of 16 tumor cell lines induced M differentiation due to secreted M-CSF isoforms, including high molecular mass species. A global gene profiling of tumor-conditioned M was performed. Comparison with other datasets (polarized M1-M, M2-M, and TAMs isolated from human tumors) highlighted the upregulation of several genes also shared by TAM and M2-polarized M. The most expressed genes were selenoprotein 1, osteoactivin, osteopontin, and, interestingly, migration-stimulating factor (MSF), a poorly studied oncofoetal isoform of fibronectin. MSF (present in fetal/cancer epithelial and stromal cells but not in healthy tissues) was never identified in M. MSF production was confirmed by immunohistochemistry in human TAMs. MSF was induced by M-CSF, IL-4, and TGFbeta but not by proinflammatory stimuli. RNA and protein analysis clearly demonstrated that it is specifically associated with the M2 polarization of M. Tumor-conditioned M-derived MSFs strongly stimulated tumor cell migration, thus contributing to the motile phenotype of neoplastic cells. In conclusion, MSF is a new molecule associated with the M2 polarization of M and expressed by TAMs. Its biological function may contribute to M-mediated promotion of cancer cell invasion and metastasis.


Assuntos
Biomarcadores Tumorais/metabolismo , Movimento Celular/imunologia , Polaridade Celular/imunologia , Citocinas/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Proteínas de Neoplasias/metabolismo , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/fisiologia , Diferenciação Celular/imunologia , Linhagem Celular Transformada , Linhagem Celular Tumoral , Células Cultivadas , Técnicas de Cocultura , Meios de Cultivo Condicionados/farmacologia , Citocinas/biossíntese , Citocinas/fisiologia , Fibronectinas , Células HCT116 , Células HT29 , Humanos , Macrófagos/imunologia , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/patologia , Metástase Neoplásica/imunologia , Metástase Neoplásica/patologia , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/fisiologia
16.
J Leukoc Biol ; 111(4): 817-836, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34346525

RESUMO

The MS4A gene family encodes 18 tetraspanin-like proteins, most of which with unknown function. MS4A1 (CD20), MS4A2 (FcεRIß), MS4A3 (HTm4), and MS4A4A play important roles in immunity, whereas expression and function of other members of the family are unknown. The present investigation was designed to obtain an expression fingerprint of MS4A family members, using bioinformatics analysis of public databases, RT-PCR, and protein analysis when possible. MS4A3, MS4A4A, MS4A4E, MS4A6A, MS4A7, and MS4A14 were expressed by myeloid cells. MS4A6A and MS4A14 were expressed in circulating monocytes and decreased during monocyte-to-Mϕ differentiation in parallel with an increase in MS4A4A expression. Analysis of gene expression regulation revealed a strong induction of MS4A4A, MS4A6A, MS4A7, and MS4A4E by glucocorticoid hormones. Consistently with in vitro findings, MS4A4A and MS4A7 were expressed in tissue Mϕs from COVID-19 and rheumatoid arthritis patients. Interestingly, MS4A3, selectively expressed in myeloid precursors, was found to be a marker of immature circulating neutrophils, a cellular population associated to COVID-19 severe disease. The results reported here show that members of the MS4A family are differentially expressed and regulated during myelomonocytic differentiation, and call for assessment of their functional role and value as therapeutic targets.


Assuntos
COVID-19 , Proteínas de Membrana , Antígenos CD20 , Família , Humanos , Proteínas de Membrana/genética , Monócitos/metabolismo
17.
Front Immunol ; 12: 666198, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093560

RESUMO

Klebsiella pneumoniae is a common pathogen in human sepsis. The emergence of multidrug-resistant K. pneumoniae strains represents a major clinical challenge in nosocomial and community acquired infections. The long pentraxin PTX3, a key component of humoral innate immunity, is involved in resistance to selected pathogens by promoting opsonophagocytosis. We investigated the relevance of PTX3 in innate immunity against K. pneumoniae infections using Ptx3-/- mice and mouse models of severe K. pneumoniae infections. Local and systemic PTX3 expression was induced following K. pneumoniae pulmonary infection, in association with the up-regulation of TNF-α and IL-1ß. PTX3 deficiency in mice was associated with higher bacterial burden and mortality, release of pro-inflammatory cytokines as well as IL-10 in the lung and systemically. The analysis of the mechanisms responsible of PTX3-dependent control of K. pneumoniae infection revealed that PTX3 did not interact with K. pneumoniae, or promote opsonophagocytosis. The comparison of susceptibility of wild-type, Ptx3-/-, C3-/- and Ptx3-/- /C3-/- mice to the infection showed that PTX3 acted in a complement-independent manner. Lung histopathological analysis showed more severe lesions in Ptx3-/- mice with fibrinosuppurative, necrotizing and haemorrhagic bronchopneumonia, associated with increased fibrin deposition in the lung and circulating fibrinogen consumption. These findings indicate that PTX3 contributes to the control of K. pneumoniae infection by modulating inflammatory responses and tissue damage. Thus, this study emphasizes the relevance of the role of PTX3 as regulator of inflammation and orchestrator of tissue repair in innate responses to infections.


Assuntos
Proteína C-Reativa/imunologia , Infecções por Klebsiella/imunologia , Klebsiella pneumoniae/patogenicidade , Componente Amiloide P Sérico/imunologia , Animais , Carga Bacteriana/imunologia , Proteína C-Reativa/deficiência , Proteína C-Reativa/metabolismo , Citocinas/metabolismo , Fibrina/metabolismo , Fibrinogênio/metabolismo , Imunidade Inata , Inflamação , Infecções por Klebsiella/metabolismo , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/patologia , Klebsiella pneumoniae/imunologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Sepse/imunologia , Sepse/metabolismo , Sepse/microbiologia , Sepse/patologia , Componente Amiloide P Sérico/deficiência , Componente Amiloide P Sérico/metabolismo , Células Estromais/metabolismo
18.
Nat Cancer ; 2(2): 218-232, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-34505065

RESUMO

Complement has emerged as a component of tumor promoting inflammation. We conducted a systematic assessment of the role of complement activation and effector pathways in sarcomas. C3-/-, MBL1/2-/- and C4-/- mice showed reduced susceptibility to 3-methylcholanthrene sarcomagenesis and transplanted sarcomas, whereas C1q and factor B deficiency had marginal effects. Complement 3a receptor (C3aR), but not C5aR1 and C5aR2, deficiency mirrored the phenotype of C3-/- mice. C3 and C3aR deficiency were associated with reduced accumulation and functional skewing of tumor-associated macrophages, increased T cell activation and response to anti-PD-1 therapy. Transcriptional profiling of sarcoma infiltrating macrophages and monocytes revealed the enrichment of MHC II-dependent antigen presentation pathway in C3-deficient cells. In patients, C3aR expression correlated with a macrophage population signature and C3 deficiency-associated signatures predicted better clinical outcome. These results suggest that the lectin pathway and C3a/C3aR axis are key components of complement and macrophage-mediated sarcoma promotion and immunosuppression.


Assuntos
Lectinas , Receptores de Complemento/metabolismo , Sarcoma , Animais , Ativação do Complemento/fisiologia , Humanos , Terapia de Imunossupressão , Lectinas/metabolismo , Camundongos , Monócitos/metabolismo , Receptor da Anafilatoxina C5a/metabolismo , Sarcoma/tratamento farmacológico
19.
Circulation ; 120(8): 699-708, 2009 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-19667236

RESUMO

BACKGROUND: Immune responses participate in several phases of atherosclerosis; there is, in fact, increasing evidence that both adaptive immunity and innate immunity tightly regulate atherogenesis. Pentraxins are a superfamily of acute-phase proteins that includes short pentraxins such as C-reactive protein or long pentraxins such as PTX3, a molecule acting as the humoral arm of innate immunity. To address the potential role of PTX3 in atherogenesis, we first investigated the expression of PTX3 during atherogenesis, generated double-knockout mice lacking PTX3 and apolipoprotein E, and then studied the effect of murine PTX3 deficiency on plasma lipids, atherosclerosis development, and gene expression pattern in the vascular wall. METHODS AND RESULTS: PTX3 expression increases in the vascular wall of apolipoprotein E-knockout mice from 3 up to 18 months of age. Double-knockout mice lacking PTX3 and apolipoprotein E were fed an atherogenic diet for 16 weeks. Aortic lesions were significantly increased in double-knockout mice and mice heterozygous for PTX3 compared with apolipoprotein E-knockout mice. Mice lacking PTX3 showed a more pronounced inflammatory profile in the vascular wall as detected by cDNA microarray and quantitative polymerase chain reaction analysis and an increased macrophage accumulation within the plaque. Finally, lesion size correlated with the number of bone marrow monocytes. CONCLUSIONS: PTX3 has atheroprotective effects in mice, which, in light of the cardioprotective effects recently reported, suggests a cardiovascular protective function of the long pentraxin 3 through the modulation of the immunoinflammatory balance in the cardiovascular system.


Assuntos
Aterosclerose/genética , Aterosclerose/imunologia , Proteína C-Reativa/genética , Proteína C-Reativa/imunologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Vasculite/genética , Vasculite/imunologia , Animais , Aorta/patologia , Aorta/fisiologia , Apolipoproteínas E/genética , Aterosclerose/patologia , Peso Corporal , Feminino , Expressão Gênica/imunologia , Lipídeos/sangue , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout , Fatores Sexuais , Vasculite/patologia
20.
Blood ; 112(9): 3723-34, 2008 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-18694997

RESUMO

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that patrol tissues to sense danger signals and activate specific immune responses. In addition, they also play a role in inflammation and tissue repair. Here, we show that oxygen availability is necessary to promote full monocyte-derived DC differentiation and maturation. Low oxygen tension (hypoxia) inhibits expression of several differentiation and maturation markers (CD1a, CD40, CD80, CD83, CD86, and MHC class II molecules) in response to lipopolysaccharide (LPS), as well as their stimulatory capacity for T-cell functions. These events are paralleled by impaired up-regulation of the chemokine receptor CCR7, an otherwise necessary event for the homing of mature DCs to lymph nodes. In contrast, hypoxia strongly up-regulates production of proinflammatory cytokines, particularly TNFalpha and IL-1beta, as well as the inflammatory chemokine receptor CCR5. Subcutaneous injection of hypoxic DCs into the footpads of mice results in defective DC homing to draining lymph nodes, but enhanced leukocyte recruitment at the site of injection. Thus, hypoxia uncouples the promotion of inflammatory and tissue repair from sentinel functions in DCs, which we suggest is a safeguard mechanism against immune reactivity to damaged tissues.


Assuntos
Hipóxia Celular/imunologia , Hipóxia Celular/fisiologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Quimiocinas/metabolismo , Quimiotaxia , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Ligantes , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/citologia , Monócitos/imunologia , Monócitos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Toll-Like/agonistas , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo
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