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1.
EMBO Rep ; 25(4): 1886-1908, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38413734

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a dismal prognosis that arises from precursor lesions called pancreatic intraepithelial neoplasias (PanINs). Progression from low- to high-grade PanINs is considered as tumor initiation, and a deeper understanding of this switch is needed. Here, we show that synaptic molecule neuroligin-2 (NLGN2) is expressed by pancreatic exocrine cells and plays a crucial role in the regulation of contact inhibition and epithelial polarity, which characterize the switch from low- to high-grade PanIN. NLGN2 localizes to tight junctions in acinar cells, is diffusely distributed in the cytosol in low-grade PanINs and is lost in high-grade PanINs and in a high percentage of advanced PDACs. Mechanistically, NLGN2 is necessary for the formation of the PALS1/PATJ complex, which in turn induces contact inhibition by reducing YAP function. Our results provide novel insights into NLGN2 functions outside the nervous system and can be used to model PanIN progression.


Assuntos
Carcinoma in Situ , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neuroliginas , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma in Situ/patologia , Transformação Celular Neoplásica
2.
Eur J Immunol ; 53(12): e2350507, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37713238

RESUMO

Osteoarthritis (OA) is characterized by an abundance of inflammatory M1-like macrophages damaging local tissues. The search for new potential drugs for OA suffers from the lack of appropriate methods of long-lasting inflammation. Here we developed and characterized an in vitro protocol of long-lasting culture of primary human monocyte-derived macrophages differentiated with a combination of M-CSF+GM-CSF that optimally supported long-cultured macrophages (LC-Mϕs) for up to 15 days, unlike their single use. Macrophages repeatedly stimulated for 15 days with the TLR2 ligand Pam3CSK4 (LCS-Mϕs), showed sustained levels over time of IL-6, CCL2, and CXCL8, inflammatory mediators that were also detected in the synovial fluids of OA patients. Furthermore, macrophages isolated from the synovia of two OA patients showed an expression profile of inflammation-related genes similar to that of LCS-Mϕs, validating our protocol as a model of chronically activated inflammatory macrophages. Next, to confirm that these LCS-Mϕs could be modulated by anti-inflammatory compounds, we employed dexamethasone and/or celecoxib, two drugs widely used in OA treatment, that significantly inhibited the production of inflammatory mediators. This easy-to-use in vitro protocol of long-lasting inflammation with primary human macrophages could be useful for the screening of new compounds to improve the therapy of inflammatory disorders.


Assuntos
Osteoartrite , Agonistas do Receptor Semelhante a Toll , Humanos , Macrófagos/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo
3.
Nanomedicine ; 55: 102719, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37977510

RESUMO

Chronic inflammatory diseases are increasing in developed societies, thus new anti-inflammatory approaches are needed in the clinic. Synthetic peptides complexes can be designed to mimic the activity of anti-inflammatory mediators, in order to alleviate inflammation. Here, we evaluated the anti-inflammatory efficacy of tethered peptides mimicking the interleukin-1 receptor antagonist (IL-1Ra) and the heat-shock protein 70 (HSP70). We tested their biocompatibility and anti-inflammatory activity in vitro in primary human monocytes and differentiated macrophages activated with two different stimuli: the TLR agonists (LPS + IFN-γ) or Pam3CSK4. Our results demonstrate that IL-1Ra and HSP70 synthetic peptides present a satisfactory biocompatible profile and significantly inhibit the secretion of several pro-inflammatory cytokines (IL-6, IL-8, IL-1ß and TNFα). We further confirmed their anti-inflammatory activity when peptides were coated on a biocompatible material commonly employed in surgical implants. Overall, our findings support the potential use of IL-1Ra and HSP70 synthetic peptides for the treatment of inflammatory conditions.


Assuntos
Anti-Inflamatórios , Proteína Antagonista do Receptor de Interleucina 1 , Humanos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Peptídeos/farmacologia , Peptídeos/uso terapêutico
4.
Blood ; 138(21): 2093-2105, 2021 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-34125889

RESUMO

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.


Assuntos
Hematopoiese Clonal , Mutação , Fatores Etários , Idoso de 80 Anos ou mais , Artrite Reumatoide/etiologia , Artrite Reumatoide/genética , Doença das Coronárias/etiologia , Doença das Coronárias/genética , Feminino , Humanos , Leucemia Mieloide/etiologia , Leucemia Mieloide/genética , Masculino , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/genética
5.
Eur J Immunol ; 51(11): 2677-2686, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34570376

RESUMO

A considerable proportion of cancer patients are resistant or only partially responsive to immune checkpoint blockade immunotherapy. Tumor-Associated Macrophages (TAMs) infiltrating the tumor stroma suppress the adaptive immune responses and, hence, promote tumor immune evasion. Depletion of TAMs or modulation of their protumoral functions is actively pursued, with the purpose of relieving this state of immunesuppression. We previously reported that trabectedin, a registered antitumor compound, selectively reduces monocytes and TAMs in treated tumors. However, its putative effects on the adaptive immunity are still unclear. In this study, we investigated whether treatment of tumor-bearing mice with trabectedin modulates the presence and functional activity of T-lymphocytes. In treated tumors, there was a significant upregulation of T cell-associated genes, including CD3, CD8, perforin, granzyme B, and IFN-responsive genes (MX1, CXCL10, and PD-1), indicating that T lymphocytes were activated after treatment. Notably, the mRNA levels of the Pdcd1 gene, coding for PD-1, were strongly increased. Using a fibrosarcoma model poorly responsive to PD-1-immunotherapy, treatment with trabectedin prior to anti-PD-1 resulted in improved antitumor efficacy. In conclusion, pretreatment with trabectedin enhances the therapeutic response to checkpoint inhibitor-based immunotherapy. These findings provide a good rational for the combination of trabectedin with immunotherapy regimens.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Antineoplásicos Alquilantes/farmacologia , Neoplasias Experimentais/imunologia , Trabectedina/farmacologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Animais , Fibrossarcoma/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia
7.
Int J Mol Sci ; 23(10)2022 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-35628597

RESUMO

Pleural mesothelioma (PM) is an aggressive tumor with few therapeutic options. Although patients with epithelioid PM (ePM) survive longer than non-epithelioid PM (non-ePM), heterogeneity of tumor response in ePM is observed. The role of the tumor immune microenvironment (TIME) in the development and progression of PM is currently considered a promising biomarker. A few studies have used high-throughput technologies correlated with TIME evaluation and morphologic and clinical data. This study aimed to identify different morphological, immunohistochemical, and transcriptional profiles that could potentially predict the outcome. A retrospective multicenter cohort of 129 chemonaive PM patients was recruited. Tissue slides were reviewed by dedicated pathologists for histotype classification and immunophenotype of tumor-infiltrating lymphocytes (TILs) and lymphoid aggregates or tertiary lymphoid structures (TLS). ePM (n = 99) survivors were further classified into long (>36 months) or short (<12 months) survivors. RNAseq was performed on a subset of 69 samples. Distinct transcriptional profiling in long and short ePM survivors was found. An inflammatory background with a higher number of B lymphocytes and a prevalence of TLS formations were detected in long compared to short ePM survivors. These results suggest that B cell infiltration could be important in modulating disease aggressiveness, opening a pathway for novel immunotherapeutic approaches.


Assuntos
Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Estruturas Linfoides Terciárias , Humanos , Mesotelioma/genética , Neoplasias Pleurais/genética , Sobreviventes , Estruturas Linfoides Terciárias/patologia , Microambiente Tumoral/genética
8.
Mol Med ; 27(1): 121, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34583655

RESUMO

Myeloid cells infiltrating tumors are gaining ever growing attention in the last years because their pro-tumor and immunosuppressive functions are relevant for disease progression and therapeutic responses. The functional ambiguity of tumor-associated macrophages (TAMs), mostly promoting tumor evolution, is a challenging hurdle. This is even more evident in the case of cancer stem cells (CSCs); as active participants in the specialized environment of the cancer stem cell niche, TAMs initiate a reciprocal conversation with CSCs. TAMs contribute to protect CSCs from the hostile environment (exogenous insults, toxic compounds, attacks from the immune cells), and produce several biologically active mediators that modulate crucial developmental pathways that sustain cancer cell stemness. In this review, we have focused our attention on the interaction between TAMs and CSCs; we describe how TAMs impact on CSC biology and, in turn, how CSCs exploit the tissue trophic activity of macrophages to survive and progress. Since CSCs are responsible for therapy resistance and tumor recurrence, they are important therapeutic targets. In view of the recent success in oncology obtained by stimulating the immune system, we discuss some macrophage-targeted therapeutic strategies that may also affect the CSCs and interrupt their malevolent alliance.


Assuntos
Comunicação Celular/imunologia , Neoplasias/imunologia , Células-Tronco Neoplásicas/imunologia , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Sobrevivência Celular/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Progressão da Doença , Humanos , Ativação de Macrófagos/imunologia , Modelos Imunológicos , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco Neoplásicas/metabolismo , Evasão Tumoral/imunologia , Macrófagos Associados a Tumor/classificação , Macrófagos Associados a Tumor/metabolismo
9.
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
10.
Semin Immunol ; 34: 103-113, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28941641

RESUMO

The engineering of new nanomedicines with ability to target and kill or re-educate Tumor Associated Macrophages (TAMs) stands up as a promising strategy to induce the effective switching of the tumor-promoting immune suppressive microenvironment, characteristic of tumors rich in macrophages, to one that kills tumor cells, is anti-angiogenic and promotes adaptive immune responses. Alternatively, the loading of monocytes/macrophages in blood circulation with nanomedicines, may be used to profit from the high infiltration ability of myeloid cells and to allow the drug release in the bulk of the tumor. In addition, the development of TAM-targeted imaging nanostructures, can be used to study the macrophage content in solid tumors and, hence, for a better diagnosis and prognosis of cancer disease. The major challenges for the effective targeting of TAM with nanomedicines and their application in the clinic have already been identified. These challenges are associated to the undesirable clearance of nanomedicines by, the mononuclear phagocyte system (macrophages) in competing organs (liver, lung or spleen), upon their intravenous injection; and also to the difficult penetration of nanomedicines across solid tumors due to the abnormal vasculature and the excessive extracellular matrix present in stromal tumors. In this review we describe the recent nanotechnology-base strategies that have been developed to target macrophages in tumors.


Assuntos
Imunoterapia/métodos , Macrófagos/imunologia , Sistema Fagocitário Mononuclear , Nanopartículas/uso terapêutico , Nanoestruturas/estatística & dados numéricos , Neoplasias/imunologia , Animais , Citotoxicidade Imunológica , Sistemas de Liberação de Medicamentos , Humanos , Nanomedicina , Microambiente Tumoral
11.
Eur J Immunol ; 49(5): 801-811, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30779113

RESUMO

Macrophage plasticity is the ability of mononuclear phagocytes to change phenotype, function, and genetic reprogramming upon encounter of specific local stimuli. In the tumor microenvironment, Tumor-Associated Macrophages (TAMs) acquire an immune-suppressive and tumor-promoting phenotype. With the aim to re-educate TAMs to antitumor effectors, in this study, we used two immunestimulatory compounds: the TLR7 agonist Imiquimod (IMQ) and the TLR3 agonist Poly(I:C). To better mimic in vitro the response of TAMs, we used Tumor-Conditioned Macrophages (TC-Mϕ) differentiated in the presence of tumor cell supernatants. Our results show that TC-Mϕ respond differently from conventional M2-polarized macrophages. Upon stimulation with IMQ, TC-Mϕ did not upregulate major histocompatibility complex (MHC II) molecules and unexpectedly expressed increased CD206. With both compounds, TC-Mϕ produced higher levels of inflammatory cytokines than M2 macrophages. IMQ and Poly(I:C) differed in the types of regulated genes and secreted mediators. Reflecting their signaling pathways, only IMQ significantly induced IL-1ß and IL-6, while only Poly(I:C) stimulated CXCL10, and both upregulated CCL5. Of note, using a novel cytotoxicity assay, Poly(I:C), but not IMQ, was effective in triggering the cytotoxic activity of TC-Mϕ against cancer cells. Overall, the results demonstrate that Poly(I:C) stimulation of TC-Mϕ is superior than IMQ in terms of macrophage re-education toward antitumor effectors.


Assuntos
Antineoplásicos/farmacologia , Imiquimode/farmacologia , Macrófagos/imunologia , Neoplasias/imunologia , Poli I-C/farmacologia , Linhagem Celular Tumoral , Membrana Celular/imunologia , Membrana Celular/metabolismo , Citocinas/metabolismo , Humanos , Imiquimode/imunologia , Imunomodulação , Macrófagos/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Poli I-C/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
12.
Int J Mol Sci ; 21(14)2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32650452

RESUMO

Intestinal macrophages are key players in the regulation of the oral tolerance, controlling gut homeostasis by discriminating innocuous antigens from harmful pathogens. Diet exerts a significant impact on human health, influencing the composition of gut microbiota and the developing of several non-communicable diseases, including cancer. Nutrients and microbiota are able to modify the profile of intestinal macrophages, shaping their key function in the maintenance of the gut homeostasis. Intestinal disease often occurs as a breakdown of this balance: defects in monocyte-macrophage differentiation, wrong dietary habits, alteration of microbiota composition, and impairment in the resolution of inflammation may contribute to the development of intestinal chronic inflammation and colorectal cancer. Accordingly, dietary interventions and macrophage-targeted therapies are emerging as innovative tools for the treatment of several intestinal pathologies. In this review, we will describe the delicate balance between diet, microbiota and intestinal macrophages in homeostasis and how the perturbation of this equilibrium may lead to the occurrence of inflammatory conditions in the gut. The understanding of the molecular pathways and dietary factors regulating the activity of intestinal macrophages might result in the identification of innovative targets for the treatments of intestinal pathologies.


Assuntos
Neoplasias Colorretais/patologia , Inflamação/patologia , Intestinos/patologia , Macrófagos/patologia , Animais , Dieta/métodos , Microbioma Gastrointestinal/fisiologia , Homeostase/fisiologia , Humanos
13.
J Immunol ; 196(2): 902-14, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26673138

RESUMO

Human colorectal cancer (CRC) is a frequent neoplasia in Western countries, and its metastatic progression is a major cause of cancer-related death. In search of specific molecules upregulated in CRC, with possible clinical relevance, we performed a differential gene-profiling analysis in surgery-derived CRC samples and adjacent uninvolved intestinal mucosa. The chemokine CX3CL1 and its specific receptor CX3CR1 were significantly upregulated in tumors. Higher expression of CX3CL1 and CX3CR1 was confirmed by immunohistochemistry in 100 CRC tumor samples (stages I-III). Unexpectedly, high immune scores of CX3CL1 did not correlate with the density of tumor-infiltrating CD3(+) T cells or CD68(+) macrophages. Coexpression of ligand and receptor by tumor cells (axis-positive tumors) significantly associated with longer disease-free (p = 0.01) and disease-specific survival (p = 0.001). Conversely, axis-negative tumors (with low expression of both ligand and receptor) had increased risk of tumor relapse (p = 0.02), and increased likelihood of metachronous metastasis (p = 0.001), including after stage adjustment (p = 0.006). Transduction of CX3CL1 and CX3CR1 in CRC tumor cell lines induced cell aggregation that strongly inhibited in vitro migration in chemotaxis assays. In a mouse model of spleen-liver metastases, cancer dissemination to liver was dramatically reduced in CX3CL1-CX3CR1-expressing tumors, and ligand-receptor interaction was confirmed in cancer cells in vivo by fluorescence resonance energy transfer analysis. In conclusion, tumoral expression of the CX3CL1-CX3CR1 chemokine axis functions as a retention factor, increasing homotypic cell adhesion and limiting tumor spreading to metastatic sites. Lack or low levels of expression of CX3CL1-CX3CR1 by tumor cells identifies a group of CRC patients at increased risk of metastatic progression.


Assuntos
Quimiocina CX3CL1/biossíntese , Neoplasias Colorretais/patologia , Invasividade Neoplásica/patologia , Receptores de Quimiocinas/biossíntese , Animais , Receptor 1 de Quimiocina CX3C , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Feminino , Transferência Ressonante de Energia de Fluorescência , Imunofluorescência , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Camundongos Nus , Metástase Neoplásica , Reação em Cadeia da Polimerase , Prognóstico , Modelos de Riscos Proporcionais , Transcriptoma
14.
Br J Cancer ; 117(5): 628-638, 2017 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-28683469

RESUMO

BACKGROUND: Lurbinectedin is a novel anticancer agent currently undergoing late-stage (Phase II /III) clinical evaluation in platinum-resistant ovarian, BRCA1/2-mutated breast and small-cell lung cancer. Lurbinectedin is structurally related to trabectedin and it inhibits active transcription and the DNA repair machinery in tumour cells. METHODS: In this study we investigated whether lurbinectedin has the ability to modulate the inflammatory microenvironment and the viability of myeloid cells in tumour-bearing mice. RESULTS: Administration of lurbinectedin significantly and selectively decreased the number of circulating monocytes and, in tumour tissues, that of macrophages and vessels. Similar findings were observed when a lurbinectedin-resistant tumour variant was used, indicating a direct effect of lurbinectedin on the tumour microenviroment. In vitro, lurbinectedin induced caspase-8-dependent apoptosis of human purified monocytes, whereas at low doses it significantly inhibited the production of inflammatory/growth factors (CCL2, CXCL8 and VEGF) and dramatically impaired monocyte adhesion and migration ability. These findings were supported by the strong inhibition of genes of the Rho-GTPase family in lurbinectedin-treated monocytes. CONCLUSIONS: The results illustrate that lurbinectedin affects at multiple levels the inflammatory microenvironment by acting on the viability and functional activity of mononuclear phagocytes. These peculiar effects, combined with its intrinsic activity against cancer cells, make lurbinectedin a compound of particular interest in oncology.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Carbolinas/farmacologia , Fibrossarcoma/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Macrófagos , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , Neoplasias Ovarianas/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos Alquilantes/uso terapêutico , Apoptose/efeitos dos fármacos , Carbolinas/uso terapêutico , Caspase 8/metabolismo , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Quimiocina CCL2/biossíntese , Dioxóis/farmacologia , Regulação para Baixo , Feminino , Fibrossarcoma/imunologia , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Células HL-60 , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Interleucina-8/biossíntese , Contagem de Leucócitos , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Neovascularização Patológica/prevenção & controle , Tetra-Hidroisoquinolinas/farmacologia , Trabectedina , Microambiente Tumoral/imunologia , Células U937 , Fator A de Crescimento do Endotélio Vascular/biossíntese , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas rho de Ligação ao GTP/genética
15.
Br J Cancer ; 116(3): 335-343, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28072764

RESUMO

BACKGROUND: Juvenile myelomonocytic leukaemia (JMML) and chronic myelomonocytic leukaemia (CMML) are myelodysplastic myeloproliferative (MDS/MPN) neoplasms with unfavourable prognosis and without effective chemotherapy treatment. Trabectedin is a DNA minor groove binder acting as a modulator of transcription and interfering with DNA repair mechanisms; it causes selective depletion of cells of the myelomonocytic lineage. We hypothesised that trabectedin might have an antitumour effect on MDS/MPN. METHODS: Malignant CD14+ monocytes and CD34+ haematopoietic progenitor cells were isolated from peripheral blood/bone marrow mononuclear cells. The inhibition of CFU-GM colonies and the apoptotic effect on CD14+ and CD34+ induced by trabectedin were evaluated. Trabectedin's effects were also investigated in vitro on THP-1, and in vitro and in vivo on MV-4-11 cell lines. RESULTS: On CMML/JMML cells, obtained from 20 patients with CMML and 13 patients with JMML, trabectedin - at concentration pharmacologically reasonable, 1-5 nM - strongly induced apoptosis and inhibition of growth of haematopoietic progenitors (CFU-GM). In these leukaemic cells, trabectedin downregulated the expression of genes belonging to the Rho GTPases pathway (RAS superfamily) having a critical role in cell growth and cytoskeletal dynamics. Its selective activity on myelomonocytic malignant cells was confirmed also on in vitro THP-1 cell line and on in vitro and in vivo MV-4-11 cell line models. CONCLUSIONS: Trabectedin could be good candidate for clinical studies in JMML/CMML patients.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dioxóis/uso terapêutico , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucemia Mielomonocítica Juvenil/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/patologia , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/patologia , Camundongos , Camundongos Nus , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Trabectedina , Ensaio Tumoral de Célula-Tronco
16.
Cell Mol Life Sci ; 73(13): 2411-24, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26956893

RESUMO

Myeloid cells infiltrating the tumor microenvironment, especially tumor-associated macrophages (TAMs), are essential providers of cancer-related inflammation, a condition known to accelerate tumor progression and limit the response to anti-tumor therapies. As a matter of fact, TAMs may have a dual role while interfering with cancer treatments, as they can either promote or impair their functionality. Here we review the connection between macrophages and anticancer therapies; moreover, we provide an overview of the different strategies to target or re-program TAMs for therapeutic purposes.


Assuntos
Inflamação/complicações , Macrófagos/patologia , Neoplasias/complicações , Neoplasias/terapia , Animais , Técnicas de Reprogramação Celular/métodos , Humanos , Imunoterapia/métodos , Inflamação/imunologia , Inflamação/patologia , Inflamação/terapia , Macrófagos/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Neovascularização Patológica/complicações , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Neovascularização Patológica/terapia , Microambiente Tumoral
17.
Gut ; 65(10): 1710-20, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26156960

RESUMO

OBJECTIVE: Tumour-associated macrophages (TAMs) play key roles in tumour progression. Recent evidence suggests that TAMs critically modulate the efficacy of anticancer therapies, raising the prospect of their targeting in human cancer. DESIGN: In a large retrospective cohort study involving 110 patients with pancreatic ductal adenocarcinoma (PDAC), we assessed the density of CD68-TAM immune reactive area (%IRA) at the tumour-stroma interface and addressed their prognostic relevance in relation to postsurgical adjuvant chemotherapy (CTX). In vitro, we dissected the synergism of CTX and TAMs. RESULTS: In human PDAC, TAMs predominantly exhibited an immunoregulatory profile, characterised by expression of scavenger receptors (CD206, CD163) and production of interleukin 10 (IL-10). Surprisingly, while the density of TAMs associated to worse prognosis and distant metastasis, CTX restrained their protumour prognostic significance. High density of TAMs at the tumour-stroma interface positively dictated prognostic responsiveness to CTX independently of T-cell density. Accordingly, in vitro, gemcitabine-treated macrophages became tumoricidal, activating a cytotoxic gene expression programme, inhibiting their protumoural effect and switching to an antitumour phenotype. In patients with human PDAC, neoadjuvant CTX was associated to a decreased density of CD206(+) and IL-10(+) TAMs at the tumour-stroma interface. CONCLUSIONS: Overall, our data highlight TAMs as critical determinants of prognostic responsiveness to CTX and provide clinical and in vitro evidence that CTX overall directly re-educates TAMs to restrain tumour progression. These results suggest that the quantification of TAMs could be exploited to select patients more likely to respond to CTX and provide the basis for novel strategies aimed at re-educating macrophages in the context of CTX.


Assuntos
Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Carcinoma Ductal Pancreático , Quimioterapia Adjuvante/métodos , Macrófagos/imunologia , Pancreatectomia/métodos , Neoplasias Pancreáticas , Adulto , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Feminino , Humanos , Interleucina-10/análise , Itália , Lectinas Tipo C/análise , Masculino , Receptor de Manose , Lectinas de Ligação a Manose/análise , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Seleção de Pacientes , Prognóstico , Receptores de Superfície Celular/análise , Reprodutibilidade dos Testes , Estudos Retrospectivos , Estatística como Assunto , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
18.
Int J Cancer ; 138(4): 983-91, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26348770

RESUMO

There is a well-established link between inflammation and cancer of various organs, but little data are available on inflammation-associated markers of diagnostic and prognostic clinical utility in pulmonary malignancy. Blood samples were prospectively collected from 75 resectable lung cancer patients before surgery and in a cohort of 1,358 high-risk subjects. Serum levels of long pentraxin 3 (PTX3) were determined by high-sensitivity ELISA. PTX3 immunostaining was evaluated by immunohistochemistry in cancer tissue. Serum PTX3 levels in the high-risk population were not predictive of developing subsequent lung cancer or any other malignancy; however, serum PTX3 values in patients with lung cancer were significantly higher compared with cancer-free heavy smokers. With a cutoff of 4.5 ng/ml, specificity was 0.80, sensitivity 0.69, positive predictive value 0.15 and negative predictive value 0.98. The receiver operating curve (ROC) for serum PTX3 had an area under the curve (AUC) of 83.52%. Preoperative serum PTX3 levels in lung cancer patients did not correlate with patient outcome, but high interstitial expression of PTX3 in resected tumor specimens was a significant independent prognostic factor associated with shorter survival (p < 0.001). These results support the potential of serum PTX3 as a lung cancer biomarker in high-risk subjects. Furthermore, PTX3 immunohistochemistry findings support the role of local inflammatory mechanisms in determining clinical outcome and suggest that local expression of PTX3 may be of prognostic utility in lung cancer patients.


Assuntos
Biomarcadores Tumorais/análise , Proteína C-Reativa/biossíntese , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Componente Amiloide P Sérico/biossíntese , Idoso , Área Sob a Curva , Proteína C-Reativa/análise , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Sensibilidade e Especificidade , Componente Amiloide P Sérico/análise
19.
Eur J Nucl Med Mol Imaging ; 43(11): 1954-61, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27251642

RESUMO

PURPOSE: Eliciting antitumor T-cell response by targeting the PD-1/PD-L1 axis with checkpoint inhibitors has emerged as a novel therapeutic strategy in non-small cell lung cancer (NSCLC). The identification of predictors for sensitivity or resistance to these agents is, therefore, needed. Herein, we investigate the correlation of metabolic information on FDG-PET with tissue expression of immune-checkpoints and other markers of tumor-related immunity in resected NSCLC patients. MATERIALS AND METHODS: All patients referred to our institution for upfront surgical resection of NSCLC, who were investigated with FDG-PET prior to surgery, were consecutively included in the study. From January 2010 to May 2014, 55 patients (stage IA-IIIB; M:F = 42:13; mean age 68.9 years) were investigated. Sampled surgical tumor specimens were analyzed by immunohistochemistry (IHC) for CD68-TAMs (tumor-associated macrophages), CD8-TILs (tumor infiltrating lymphocytes), PD-1-TILs, and PD-L1 tumor expression. Immunoreactivity was evaluated, and scores were compared with imaging findings. FDG-PET images were analyzed to define semi-quantitative parameters: SUVmax and SUVmean. Metabolic information on FDG-PET was correlated with tissue markers expression and disease-free survival (DFS) considering a median follow-up of 16.2 months. RESULTS: Thirty-six adenocarcinomas (ADC), 18 squamous cell carcinomas (SCC), and one sarcomatoid carcinoma were analyzed. All tumors resulted positive at FDG-PET: median SUVmax 11.3 (range: 2.3-32.5) and SUVmean 6.4 (range: 1.5-13) both resulted significantly higher in SCC compared to other NSCLC histotypes (p = 0.007 and 0.048, respectively). IHC demonstrated a median immunoreactive surface covered by CD68-TAMs of 5.41 % (range: 0.84-14.01 %), CD8-TILs of 2.9 % (range: 0.11-11.92 %), PD-1 of 0.65 % (range: 0.02-5.87 %), and PD-L1 of 0.7 % (range: 0.03-10.29 %). We found a statistically significant correlation between SUVmax and SUVmean with the expression of CD8 TILs (rho = 0.31; p = 0.027) and PD-1 (rho = 0.33; p = 0.017 and rho = 0.36; p = 0.009, respectively). The other tissue markers correlated as follows: CD8 TILs and PD-1 (rho = 0.45; p = 0.001), CD8 TILs and PD-L1 (rho = 0.41; p = 0.003), CD68-TAMs and PD-L1 (rho = 0.30; p = 0.027), PD-1 and PD-L1 (rho = 0.26; p = 0.059). With respect to patients' outcome, SUVmax, SUVmean, and disease stage showed a statistically significant correlation with DFS (p = 0.002, 0.004, and <0.001, respectively). CONCLUSIONS: The present study shows a direct association between metabolic parameters on FDG-PET and the expression of tumor-related immunity markers, suggesting a potential role for FDG-PET to characterize the tumor microenvironment and select NSCLC patients candidate to checkpoint inhibitors.


Assuntos
Biomarcadores Tumorais/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Fluordesoxiglucose F18/imunologia , Fatores Imunológicos/imunologia , Neoplasias Pulmonares/imunologia , Tomografia por Emissão de Pósitrons/métodos , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Citocinas/imunologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Imagem Molecular/métodos , Cuidados Pré-Operatórios/métodos , Compostos Radiofarmacêuticos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estatística como Assunto
20.
Cell Mol Life Sci ; 72(21): 4111-26, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26210152

RESUMO

Macrophages are cells of the innate immunity constituting the mononuclear phagocyte system and endowed with remarkable different roles essential for defense mechanisms, development of tissues, and homeostasis. They derive from hematopoietic precursors and since the early steps of fetal life populate peripheral tissues, a process continuing throughout adult life. Although present essentially in every organ/tissue, macrophages are more abundant in the gastro-intestinal tract, liver, spleen, upper airways, and brain. They have phagocytic and bactericidal activity and produce inflammatory cytokines that are important to drive adaptive immune responses. Macrophage functions are settled in response to microenvironmental signals, which drive the acquisition of polarized programs, whose extremes are simplified in the M1 and M2 dichotomy. Functional skewing of monocyte/macrophage polarization occurs in physiological conditions (e.g., ontogenesis and pregnancy), as well as in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer) and is now considered a key determinant of disease development and/or regression. Here, we will review evidence supporting a dynamic skewing of macrophage functions in disease, which may provide a basis for macrophage-centered therapeutic strategies.


Assuntos
Infecções/patologia , Macrófagos/patologia , Macrófagos/fisiologia , Neoplasias/patologia , Obesidade/patologia , Polaridade Celular , Infecções por HIV/patologia , Infecções por Helicobacter/patologia , Homeostase , Humanos , Hipersensibilidade/patologia , Infecções/microbiologia , Infecções/parasitologia , Infecções/virologia , Obesidade/metabolismo , Sepse/patologia , Tuberculose/patologia , Cicatrização
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