RESUMO
BACKGROUND: COVID-19 clinical course is highly variable and secondary infections contribute to COVID-19 complexity. Early detection of secondary infections is clinically relevant for patient outcome. Procalcitonin (PCT) and C-reactive protein (CRP) are the most used biomarkers of infections. Pentraxin 3 (PTX3) is an acute phase protein with promising performance as early biomarker in infections. In patients with COVID-19, PTX3 plasma concentrations at hospital admission are independent predictor of poor outcome. In this study, we assessed whether PTX3 contributes to early identification of co-infections during the course of COVID-19. METHODS: We analyzed PTX3 levels in patients affected by COVID-19 with (n = 101) or without (n = 179) community or hospital-acquired fungal or bacterial secondary infections (CAIs or HAIs). FINDINGS: PTX3 plasma concentrations at diagnosis of CAI or HAI were significantly higher than those in patients without secondary infections. Compared to PCT and CRP, the increase of PTX3 plasma levels was associated with the highest hazard ratio for CAIs and HAIs (aHR 11.68 and 24.90). In multivariable Cox regression analysis, PTX3 was also the most significant predictor of 28-days mortality or intensive care unit admission of patients with potential co-infections, faring more pronounced than CRP and PCT. INTERPRETATION: PTX3 is a promising predictive biomarker for early identification and risk stratification of patients with COVID-19 and co-infections. FUNDING: Dolce & Gabbana fashion house donation; Ministero della Salute for COVID-19; EU funding within the MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases (Project no. PE00000007, INF-ACT) and MUR PNRR Italian network of excellence for advanced diagnosis (Project no. PNC-E3-2022-23683266 PNC-HLS-DA); EU MSCA (project CORVOS 860044).
Assuntos
Biomarcadores , Proteína C-Reativa , COVID-19 , Coinfecção , SARS-CoV-2 , Componente Amiloide P Sérico , Humanos , COVID-19/sangue , COVID-19/diagnóstico , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análise , Componente Amiloide P Sérico/metabolismo , Biomarcadores/sangue , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , SARS-CoV-2/isolamento & purificação , Infecções Bacterianas/sangue , Infecções Bacterianas/diagnóstico , Pró-Calcitonina/sangue , Prognóstico , Micoses/sangue , Micoses/diagnóstico , Idoso de 80 Anos ou maisRESUMO
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/metabolismoRESUMO
Cancer-related inflammation is a crucial component of the tumor microenvironment (TME). Complement activation occurs in cancer and supports the development of an inflammatory microenvironment. Complement has traditionally been considered a mechanism of immune resistance against cancer, and its activation is known to contribute to the cytolytic effects of antibody-based immunotherapeutic treatments. However, several studies have recently revealed that complement activation may exert protumoral functions by sustaining cancer-related inflammation and immunosuppression through different molecular mechanisms, targeting both the TME and cancer cells. These new discoveries have revealed that complement manipulation can be considered a new strategy for cancer therapies. Here we summarize our current understanding of the mechanisms by which the different elements of the complement system exert antitumor or protumor functions, both in preclinical studies and in human tumorigenesis. Complement components can serve as disease biomarkers for cancer stratification and prognosis and be exploited for tumor treatment.
Assuntos
Neoplasias , Yin-Yang , Humanos , Proteínas do Sistema Complemento , Ativação do Complemento , Inflamação , Microambiente TumoralRESUMO
Interleukin-1 receptor family members (ILRs) and Toll-Like Receptors (TLRs) play pivotal role in immunity and inflammation and are expressed by most cell types including cells of both the innate and adaptive immune system. In this context, IL-1 superfamily members are also important players in regulating function and differentiation of adaptive and innate lymphoid cells. This system is tightly regulated in order to avoid uncontrolled activation, which may lead to detrimental inflammation contributing to autoimmune or allergic responses. IL-1R8 (also known as TIR8 or SIGIRR) is a member of the IL-1R family that acts as a negative regulator dampening ILR and TLR signaling and as a co-receptor for human IL-37. Human and mouse NK cells, that are key players in immune surveillance of tumors and infections, express high level of IL-1R8. In this review, we will summarize our current understanding on the structure, expression and function of IL-1R8 and we will also discuss the emerging role of IL-1R8 as an important checkpoint regulating NK cells function in pathological conditions including cancer and viral infections.
Assuntos
Imunidade Inata , Neoplasias , Animais , Humanos , Inflamação , Células Matadoras Naturais , Neoplasias/metabolismo , Receptores de Interleucina-1/metabolismoRESUMO
Rationale: Nanobodies (Nbs) have emerged as an elegant alternative to the use of conventional monoclonal antibodies in cancer therapy, but a detailed microscopic insight into the in vivo pharmacokinetics of different Nb formats in tumor-bearers is lacking. This is especially relevant for the recognition and targeting of pro-tumoral tumor-associated macrophages (TAMs), which may be located in less penetrable tumor regions. Methods: We employed anti-Macrophage Mannose Receptor (MMR) Nbs, in a monovalent (m) or bivalent (biv) format, to assess in vivo TAM targeting. Intravital and confocal microscopy were used to analyse the blood clearance rate and targeting kinetics of anti-MMR Nbs in tumor tissue, healthy muscle tissue and liver. Fluorescence Molecular Tomography was applied to confirm anti-MMR Nb accumulation in the primary tumor and in metastatic lesions. Results: Intravital microscopy demonstrated significant differences in the blood clearance rate and macrophage targeting kinetics of (m) and (biv)anti-MMR Nbs, both in tumoral and extra-tumoral tissue. Importantly, (m)anti-MMR Nbs are superior in reaching tissue macrophages, an advantage that is especially prominent in tumor tissue. The administration of a molar excess of unlabelled (biv)anti-MMR Nbs increased the (m)anti-MMR Nb bioavailability and impacted on its macrophage targeting kinetics, preventing their accumulation in extra-tumoral tissue (especially in the liver) but only partially influencing their interaction with TAMs. Finally, anti-MMR Nb administration not only allowed the visualization of TAMs in primary tumors, but also at a distant metastatic site. Conclusions: These data describe, for the first time, a microscopic analysis of (m) and (biv)anti-MMR Nb pharmacokinetics in tumor and healthy tissues. The concepts proposed in this study provide important knowledge for the future use of Nbs as diagnostic and therapeutic agents, especially for the targeting of tumor-infiltrating immune cells.
Assuntos
Neoplasias , Anticorpos de Domínio Único , Humanos , Receptor de Manose , Lectinas Tipo C , Lectinas de Ligação a Manose , Receptores de Superfície Celular , Macrófagos Associados a Tumor , Neoplasias/tratamento farmacológicoRESUMO
Tumour-associated macrophages are an essential component of the tumour microenvironment and have a role in the orchestration of angiogenesis, extracellular matrix remodelling, cancer cell proliferation, metastasis and immunosuppression, as well as in resistance to chemotherapeutic agents and checkpoint blockade immunotherapy. Conversely, when appropriately activated, macrophages can mediate phagocytosis of cancer cells and cytotoxic tumour killing, and engage in effective bidirectional interactions with components of the innate and adaptive immune system. Therefore, they have emerged as therapeutic targets in cancer therapy. Macrophage-targeting strategies include inhibitors of cytokines and chemokines involved in the recruitment and polarization of tumour-promoting myeloid cells as well as activators of their antitumorigenic and immunostimulating functions. Early clinical trials suggest that targeting negative regulators (checkpoints) of myeloid cell function indeed has antitumor potential. Finally, given the continuous recruitment of myelomonocytic cells into tumour tissues, macrophages are candidates for cell therapy with the development of chimeric antigen receptor effector cells. Macrophage-centred therapeutic strategies have the potential to complement, and synergize with, currently available tools in the oncology armamentarium.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Antineoplásicos/farmacologia , Imunoterapia , Macrófagos , Neoplasias/terapia , Microambiente TumoralRESUMO
BACKGROUND: More than 50% of all patients with colorectal cancer (CRC) develop liver metastases (CLM), a clinical condition characterized by poor prognosis and lack of reliable prognostic markers. Vδ1 cells are a subset of tissue-resident gamma delta (γδ) T lymphocytes endowed with a broad array of antitumor functions and showing a natural high tropism for the liver. However, little is known about their impact in the clinical outcomes of CLM. METHODS: We isolated human γδ T cells from peripheral blood (PB) and peritumoral (PT) tissue of 93 patients undergone surgical procedures to remove CLM. The phenotype of freshly purified γδ T cells was assessed by multiparametric flow cytometry, the transcriptional profiles by single cell RNA-sequencing, the functional annotations by Gene Ontology enrichment analyses and the clonotype by γδ T cell receptor (TCR)-sequencing. RESULTS: The microenvironment of CLM is characterized by a heterogeneous immune infiltrate comprising different subsets of γδ tumor-infiltrating lymphocytes (TILs) able to egress the liver and re-circulate in PB. Vδ1 T cells represent the largest population of γδ TILs within the PT compartment of CLM that is greatly enriched in Vδ1 T effector (TEF) cells expressing constitutive high levels of CD69. These Vδ1 CD69+ TILs express a distinct phenotype and transcriptional signature, show high antitumor potential and correlate with better patient clinical outcomes in terms of lower numbers of liver metastatic lesions and longer overall survival (OS). Moreover, intrahepatic CD69+ Vδ1 TILs can egress CLM tissue to re-circulate in PB, where they retain a phenotype, transcriptional signature and TCR clonal repertoires resembling their liver origin. Importantly, even the increased frequencies of the CD69+ terminally differentiated (TEMRA) Vδ1 cells in PB of patients with CLM significantly correlate with longer OS. The positive prognostic score of high frequencies of CD69+ TEMRA Vδ1 cells in PB is independent from the neoadjuvant chemotherapy and immunotherapy regimens administered to patients with CLM prior surgery. CONCLUSIONS: The enrichment of tissue-resident CD69+ Vδ1 TEMRA cells re-circulating at high frequencies in PB of patients with CLM limits tumor progression and represents a new important clinical tool to either predict the natural history of CLM or develop alternative therapeutic protocols of cellular therapies.
Assuntos
Neoplasias Colorretais , Subpopulações de Linfócitos T , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Humanos , Imunoterapia , Linfócitos do Interstício Tumoral , Receptores de Antígenos de Linfócitos T gama-delta , Subpopulações de Linfócitos T/citologia , Microambiente TumoralRESUMO
Cancer-related inflammation plays a central role in the establishment of tumor-promoting mechanisms. Tumor-associated myeloid cells, which engage in complex interactions with cancer cells, as well as stromal and tumor immune infiltrating cells, promote cancer cell proliferation and survival, angiogenesis, and the generation of an immunosuppressive microenvironment. The complement system is one of the inflammatory mechanisms activated in the tumor microenvironment. Beside exerting anti-tumor mechanisms such as complement-dependent cytotoxicity and phagocytosis induced by therapeutic monoclonal antibodies, the complement system may promote immunosuppression and tumor growth and invasiveness, in particular, through the anaphylatoxins which target both leukocytes and cancer cells. In this review, we will discuss complement-mediated mechanisms acting on leukocytes, in particular on cells of the myelomonocytic cell lineage (macrophages, neutrophils, myeloid derived suppressor cells), which promote myeloid cell recruitment and functional skewing, leading to immunosuppression and resistance to tumor-specific immunity. Pre-clinical studies, which have elucidated the role of complement in activating pro-tumor mechanisms in myeloid cells, showing the relevance of these mechanisms in human, and therapeutic approaches based on complement targeting support the hypothesis that complement directly and indirectly interferes with many of the effector pathways associated with the cancer-immunity cycle, suggesting the relevance of complement targeting to improve responses to immunotherapeutic approaches.
Assuntos
Neoplasias , Humanos , Células Mieloides , Microambiente Tumoral , Terapia de Imunossupressão , Ativação do Complemento , Proteínas do Sistema Complemento/metabolismo , ImunoterapiaRESUMO
Rationale: Sarcoidosis is a multisystemic inflammatory disease characterized by the formation of granulomas in response to persistent stimuli. The long pentraxin PTX3 (pentraxin 3) has emerged as a component of humoral innate immunity with essential functions in the resolution of inflammation, but its role during granuloma formation is unknown. Objectives: To evaluate PTX3 as a modulator of pathogenic signals involved in granuloma formation and inflammation in sarcoidosis. Methods: Peripheral blood mononuclear cells obtained from patients with sarcoidosis harboring loss-of-function genetic variants and gene-deleted mice were used to assess the role of PTX3 in experimental models of granuloma formation in vitro and in vivo. The identified mechanisms of granulomatous inflammation were further evaluated in tissue and BAL samples and correlated with the disease course. Measurements and Main Results: We have identified a molecular link between PTX3 deficiency and the pathogenic amplification of complement activation to promote granuloma formation. Mechanistically, PTX3 deficiency licensed the complement component C5a-mediated activation of the metabolic checkpoint kinase mTORC1 (mammalian target of rapamycin complex 1) and the reprogramming of macrophages toward increased glycolysis to foster their proliferation and aggregation. This process sustained the further recruitment of granuloma-promoting immune cells and the associated proinflammatory microenvironment and influenced the clinical course of the disease. Conclusions: Our results identify PTX3 as a pivotal molecule that regulates complement-mediated signaling cues in macrophages to restrain granulomatous inflammation and highlight the therapeutic potential of this signaling axis in targeting granuloma formation in sarcoidosis.
Assuntos
Proteína C-Reativa , Ativação de Macrófagos , Sarcoidose , Componente Amiloide P Sérico , Animais , Camundongos , Proteína C-Reativa/metabolismo , Proteínas do Sistema Complemento , Granuloma , Inflamação , Leucócitos Mononucleares/metabolismo , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/metabolismo , HumanosRESUMO
Cerebral Cavernous Malformation (CCM) is a brain vascular disease with various neurological symptoms. In this study, we describe the inflammatory profile in CCM and show for the first time the formation of neutrophil extracellular traps (NETs) in rodents and humans with CCM. Through RNA-seq analysis of cerebellum endothelial cells from wild-type mice and mice with an endothelial cell-specific ablation of the Ccm3 gene (Ccm3iECKO), we show that endothelial cells from Ccm3iECKO mice have an increased expression of inflammation-related genes. These genes encode proinflammatory cytokines and chemokines, as well as adhesion molecules, which promote recruitment of inflammatory and immune cells. Similarly, immunoassays showed elevated levels of these cytokines and chemokines in the cerebellum of the Ccm3iECKO mice. Consistently, both flow cytometry and immunofluorescence analysis showed infiltration of different subsets of leukocytes into the CCM lesions. Neutrophils, which are known to fight against infection through different strategies, including the formation of NETs, represented the leukocyte subset within the most pronounced increase in CCM. Here, we detected elevated levels of NETs in the blood and the deposition of NETs in the cerebral cavernomas of Ccm3iECKO mice. Degradation of NETs by DNase I treatment improved the vascular barrier. The deposition of NETs in the cavernomas of patients with CCM confirms the clinical relevance of NETs in CCM.
Assuntos
Armadilhas Extracelulares , Hemangioma Cavernoso do Sistema Nervoso Central , Animais , Proteínas Reguladoras de Apoptose/genética , Células Endoteliais/metabolismo , Armadilhas Extracelulares/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Humanos , Inflamação/patologia , Proteínas de Membrana/metabolismo , CamundongosRESUMO
The inhibitory receptor interleukin-1 receptor 8 (IL-1R8) has been recently recognized to be expressed also by human natural killer (NK) cells. This study was aimed to design and optimize IL-1R8 silencing conditions in human NK cells to precisely establish the activity of such receptor in these cells. Electroporation of freshly isolated or IL-2-cultured NK cells with small interfering RNA (siRNA), resulted in a marked, even though variable, IL-1R8-silencing. Although the expression profile revealed downregulation of most genes involved in several intracellular pathways, some genes related to proliferation, expression of some chemokine receptors, antibody-dependent cell cytotoxicity and cytotoxic activity were upregulated in IL-1R8-silenced NK cells. Furthermore, upon IL-15 activation, the majority of genes involved in NK cell function were upregulated in IL-1R8-siRNA-compared with control-siRNA-transfected NK cells. More importantly, in agreement with these findings, the reduction of IL-1R8 gene expression levels resulted in enhanced expression of NK cell activation markers, production of cytokines and chemokines, and cytotoxic activity against several NK cell targets with different susceptibility to NK-mediated lysis. Similar results were obtained following stimulation with IL-18. All together these data, deeply impacting on the main effector functions of human NK cells, can lead to a better understanding of IL-1R8-mediated regulation on these cells and to the design of new strategies for improving NK cell-mediated anti-tumor responses.
Assuntos
Antineoplásicos , Células Matadoras Naturais , Receptores Tipo I de Interleucina-1/imunologia , Citotoxicidade Celular Dependente de Anticorpos , Citocinas/metabolismo , Humanos , Ativação LinfocitáriaRESUMO
Interleukin-1 (IL-1) is a primary cytokine of innate immunity and inflammation. IL-1 belongs to a complex family including ligands with agonist activity, receptor antagonists, and an anti-inflammatory cytokine. The receptors for these ligands, the IL-1 Receptor (IL-1R) family, include signaling receptor complexes, decoy receptors, and negative regulators. Agonists and regulatory molecules co-evolved, suggesting the evolutionary relevance of a tight control of inflammatory responses, which ensures a balance between amplification of innate immunity and uncontrolled inflammation. IL-1 family members interact with innate immunity cells promoting innate immunity, as well as with innate and adaptive lymphoid cells, contributing to their differentiation and functional polarization and plasticity. Here we will review the properties of two key regulatory receptors of the IL-1 system, IL-1R2, the first decoy receptor identified, and IL-1R8, a pleiotropic regulator of different IL-1 family members and co-receptor for IL-37, the anti-inflammatory member of the IL-1 family. Their complex impact in pathology, ranging from infections and inflammatory responses, to cancer and neurologic disorders, as well as clinical implications and potential therapeutic exploitation will be presented.
Assuntos
Imunidade Inata , Inflamação/imunologia , Receptores Tipo II de Interleucina-1/metabolismo , Receptores de Interleucina-1/metabolismo , Animais , Humanos , Imunomodulação , Neoplasias/imunologia , Doenças do Sistema Nervoso/imunologiaRESUMO
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 farmacológicoRESUMO
Complement activation contributes to tumor progression in several cancer types. In this issue, Daugan and colleagues propose complement component C1s and C4d as new markers of prognosis in clear cell renal cell carcinoma. The mechanism of action of C1s involves both canonical and intracellular, noncanonical functions. The results provide new molecular targets to prevent tumor escape from immune surveillance, which leads to tumor progression.See related article by Daugan et al., p. 891 (2).
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Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/genética , Ativação do Complemento , Complemento C1s , Proteínas do Sistema Complemento , HumanosRESUMO
Serum amyloid P component (SAP, also known as Pentraxin 2; APCS gene) is a component of the humoral arm of innate immunity involved in resistance to bacterial infection and regulation of tissue remodeling. Here we investigate the role of SAP in antifungal resistance. Apcs-/- mice show enhanced susceptibility to A. fumigatus infection. Murine and human SAP bound conidia, activate the complement cascade and enhance phagocytosis by neutrophils. Apcs-/- mice are defective in vivo in terms of recruitment of neutrophils and phagocytosis in the lungs. Opsonic activity of SAP is dependent on the classical pathway of complement activation. In immunosuppressed mice, SAP administration protects hosts against A. fumigatus infection and death. In the context of a study of hematopoietic stem-cell transplantation, genetic variation in the human APCS gene is associated with susceptibility to invasive pulmonary aspergillosis. Thus, SAP is a fluid phase pattern recognition molecule essential for resistance against A. fumigatus.
Assuntos
Aspergillus fumigatus/imunologia , Aspergilose Pulmonar Invasiva/imunologia , Neutrófilos/imunologia , Componente Amiloide P Sérico/genética , Animais , Células Cultivadas , Variação Genética/genética , Humanos , Imunidade Inata/imunologia , Hospedeiro Imunocomprometido/imunologia , Aspergilose Pulmonar Invasiva/patologia , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose/imunologiaRESUMO
Interleukin-1 (IL-1) is a key orchestrator of inflammation and plays an important role in tumor progression. Based on preclinical models and human genetic associations, we surmise that targeting IL-1 should be considered in treating selected human tumors as well as in a prevention and/or interception setting.
Assuntos
Interleucina-1/metabolismo , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias/metabolismo , Microambiente TumoralRESUMO
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/patologiaAssuntos
Proteína C-Reativa/metabolismo , COVID-19/metabolismo , Pneumonia/metabolismo , Sepse/metabolismo , Componente Amiloide P Sérico/metabolismo , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Unidades de Terapia Intensiva , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , SARS-CoV-2 , Choque Séptico/metabolismoRESUMO
Myeloid cells in tumor tissues constitute a dynamic immune population characterized by a non-uniform phenotype and diverse functional activities. Both tumor-associated macrophages (TAMs), which are more abundantly represented, and tumor-associated neutrophils (TANs) are known to sustain tumor cell growth and invasion, support neoangiogenesis and suppress anticancer adaptive immune responses. In recent decades, several therapeutic approaches have been implemented in preclinical cancer models to neutralize the tumor-promoting roles of both TAMs and TANs. Some of the most successful strategies have now reached the clinic and are being investigated in clinical trials. In this review, we provide an overview of the recent literature on the ever-growing complexity of the biology of TAMs and TANs and the development of the most promising approaches to target these populations therapeutically in cancer patients.