RESUMO
Two major populations of myeloid-derived suppressor cells (MDSCs), monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) regulate immune responses in cancer and other pathologic conditions. Under physiologic conditions, Ly6C(hi)Ly6G(-) inflammatory monocytes, which are the normal counterpart of M-MDSCs, differentiate into macrophages and dendritic cells. PMN-MDSCs are the predominant group of MDSCs that accumulates in cancer. Here we show that a large proportion of M-MDSCs in tumor-bearing mice acquired phenotypic, morphological and functional features of PMN-MDSCs. Acquisition of this phenotype, but not the functional attributes of PMN-MDSCs, was mediated by transcriptional silencing of the retinoblastoma gene through epigenetic modifications mediated by histone deacetylase 2 (HDAC-2). These data demonstrate a new regulatory mechanism of myeloid cells in cancer.
Assuntos
Inativação Gênica , Genes do Retinoblastoma , Células Mieloides/patologia , Neoplasias/genética , Animais , Diferenciação Celular , Células Dendríticas/imunologia , Epigênese Genética , Macrófagos/imunologia , Camundongos , Monócitos/imunologia , Células Mieloides/metabolismo , Neoplasias/patologia , Fenótipo , Proteína do Retinoblastoma/genéticaRESUMO
Recruitment of monocytic myeloid-derived suppressor cells (MDSCs) and differentiation of tumor-associated macrophages (TAMs) are the major factors contributing to tumor progression and metastasis. We demonstrated that differentiation of TAMs in tumor site from monocytic precursors was controlled by downregulation of the activity of the transcription factor STAT3. Decreased STAT3 activity was caused by hypoxia and affected all myeloid cells but was not observed in tumor cells. Upregulation of CD45 tyrosine phosphatase activity in MDSCs exposed to hypoxia in tumor site was responsible for downregulation of STAT3. This effect was mediated by the disruption of CD45 protein dimerization regulated by sialic acid. Thus, STAT3 has a unique function in the tumor environment in controlling the differentiation of MDSC into TAM, and its regulatory pathway could be a potential target for therapy.
Assuntos
Hipóxia/imunologia , Antígenos Comuns de Leucócito/metabolismo , Macrófagos/imunologia , Monoéster Fosfórico Hidrolases/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Diferenciação Celular , Movimento Celular , Células Cultivadas , Dimerização , Feminino , Antígenos Comuns de Leucócito/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/imunologia , Monoéster Fosfórico Hidrolases/genética , Fator de Transcrição STAT3/genética , Ácidos Siálicos/metabolismo , Microambiente TumoralRESUMO
Myeloid-derived suppressor cells (MDSCs) are one of the major negative regulators of immune responses. In this issue of Immunity, Thevenot et al. (2014) showed that in tumors, the suppressive activity of MDSCs is regulated by transcription factor Chop.
Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/imunologia , Linfócitos T/imunologia , Fator de Transcrição CHOP/genética , Evasão Tumoral/imunologia , Animais , FemininoRESUMO
The tentacular system of Clytia hemisphaerica medusa (Cnidaria, Hydrozoa) has recently emerged as a promising experimental model to tackle the developmental mechanisms that regulate cell lineage progression in an early-diverging animal phylum. From a population of proximal stem cells, the successive steps of tentacle stinging cell (nematocyte) elaboration, are spatially ordered along a "cellular conveyor belt". Furthermore, the C. hemisphaerica tentacular system exhibits bilateral organisation, with two perpendicular polarity axes (proximo-distal and oral-aboral). We aimed to improve our knowledge of this cellular system by combining RNAseq-based differential gene expression analyses and expression studies of Wnt signalling genes. RNAseq comparisons of gene expression levels were performed (i) between the tentacular system and a control medusa deprived of all tentacles, nematogenic sites and gonads, and (ii) between three samples staggered along the cellular conveyor belt. The behaviour in these differential expression analyses of two reference gene sets (stem cell genes; nematocyte genes), as well as the relative representations of selected gene ontology categories, support the validity of the cellular conveyor belt model. Expression patterns obtained by in situ hybridisation for selected highly differentially expressed genes and for Wnt signalling genes are largely consistent with the results from RNAseq. Wnt signalling genes exhibit complex spatial deployment along both polarity axes of the tentacular system, with the Wnt/ß-catenin pathway probably acting along the oral-aboral axis rather than the proximo-distal axis. These findings reinforce the idea that, despite overall radial symmetry, cnidarians have a full potential for elaboration of bilateral structures based on finely orchestrated deployment of an ancient developmental gene toolkit.
Assuntos
Padronização Corporal/genética , Hidrozoários/genética , Via de Sinalização Wnt/genética , Animais , Biologia do Desenvolvimento/métodos , Expressão Gênica/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Hidrozoários/metabolismoRESUMO
Accumulation of pathologically activated immature myeloid cells with potent immune-suppressive activity is one of the major immunological hallmarks of cancer. In recent years, it became clear that in addition to their immune-suppressive activity, myeloid-derived suppressor cells (MDSCs) influence tumor progression in a variety of ways. They are directly implicated in the promotion of tumor metastases by participating in the formation of premetastatic niches, promoting angiogenesis and tumor cell invasion. In this review, we discuss recent data describing various roles of MDSCs in the formation of tumor metastases.
Assuntos
Células Mieloides/imunologia , Metástase Neoplásica/imunologia , Neoplasias/imunologia , Humanos , Invasividade Neoplásica/imunologia , Neovascularização Patológica/imunologiaRESUMO
Cross-presentation is one of the main features of dendritic cells (DCs), which is critically important for the development of spontaneous and therapy-inducible antitumor immune responses. Patients, at early stages of cancer, have normal presence of DCs. However, the difficulties in the development of antitumor responses in patients with low tumor burden raised the question of the mechanisms of DC dysfunction. In this study, we found that, in differentiated DCs, tumor-derived factors blocked the cross-presentation of exogenous Ags without inhibiting the Ag presentation of endogenous protein or peptides. This effect was caused by intracellular accumulation of different types of oxidized neutral lipids: triglycerides, cholesterol esters, and fatty acids. In contrast, the accumulation of nonoxidized lipids did not affect cross-presentation. Oxidized lipids blocked cross-presentation by reducing the expression of peptide-MHC class I complexes on the cell surface. Thus, this study suggests the novel role of oxidized lipids in the regulation of cross-presentation.
Assuntos
Apresentação de Antígeno/imunologia , Apresentação Cruzada/imunologia , Células Dendríticas/imunologia , Lipídeos/imunologia , Neoplasias/imunologia , Acetilcisteína/análogos & derivados , Acetilcisteína/farmacologia , Animais , Linhagem Celular Tumoral , Células Cultivadas , Meios de Cultivo Condicionados/metabolismo , Meios de Cultivo Condicionados/farmacologia , Inibidores de Cisteína Proteinase/farmacologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Citometria de Fluxo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Interferon gama/farmacologia , Lipídeos/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Neoplasias/metabolismo , Neoplasias/patologia , Ovalbumina/imunologia , Oxirredução , Fragmentos de Peptídeos/imunologiaRESUMO
Myeloid-derived suppressor cells (MDSC) are one of the major factors limiting the immune response in cancer. However, their role in bone marrow (BM), the site of primary localization of multiple myeloma (MM), is poorly understood. In this study, we found a significant accumulation of CD11b(+)CD14(-)CD33(+) immunosuppressive MDSC in BM of patients with newly diagnosed MM. To assess the possible role of MDSC in MM, we used immunocompetent mouse models. Immunosuppressive MDSC accumulated in BM of mice as early as 1 wk after tumor inoculation. S100A9 knockout (KO) mice, which are deficient in their ability to accumulate MDSC in tumor-bearing hosts, demonstrated reduced MDSC accumulation in BM after injection of MM cells compared with wild-type mice. Growth of the immunogenic MM cells was significantly reduced in S100A9KO mice. This effect was associated with the accumulation of Ag-specific CD8(+) T cells in BM and spleens of S100A9KO mice, but not wild-type mice, and was abrogated by the administration of anti-CD8 Ab or adoptive transfer of MDSC. Thus, the accumulation of MDSC at early stages of MM plays a critical role in MM progression and suggests that MDSC can be considered a possible therapeutic target in this disease.
Assuntos
Medula Óssea/imunologia , Medula Óssea/patologia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Células Mieloides/imunologia , Linfócitos T/imunologia , Animais , Modelos Animais de Doenças , Humanos , Imunofenotipagem , Camundongos , Camundongos Knockout , Mieloma Múltiplo/mortalidade , Células Mieloides/metabolismo , Fenótipo , Transplante IsogênicoRESUMO
Myeloid-derived suppressor cells (MDSCs) are one of the main cell populations responsible for regulating immune responses. MDSCs accumulate during tumor progression, autoimmunity, chronic infection and other pathological conditions, and can potently suppress T cell function. Recent studies have demonstrated the ability of MDSCs to modulate the activity of NK and myeloid cells and have implicated MDSCs in the induction of regulatory T cells. Here, we discuss recent findings that describe the molecular mechanisms that regulate the expansion and function of MDSCs, as well as recent attempts to use MDSCs in cell therapy for different pathologic conditions.
Assuntos
Células Mieloides/citologia , Células Mieloides/imunologia , Animais , Diferenciação Celular , Humanos , Tolerância Imunológica , Linfócitos/imunologia , Linfócitos T/imunologia , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: OX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed to promote tumor-specific immunity by effector T-cell activation and Fcγ receptor-mediated Treg depletion. This first-in-human study was conducted to determine the safety, tolerability, and preliminary efficacy of INCAGN01949. METHODS: Phase I/II, open-label, non-randomized, dose-escalation and dose-expansion study conducted in patients with advanced or metastatic solid tumors. Patients received INCAGN01949 monotherapy (7-1400 mg) in 14-day cycles while deriving benefit. Safety measures, clinical activity, pharmacokinetics, and pharmacodynamic effects were assessed and summarized with descriptive statistics. RESULTS: Eighty-seven patients were enrolled; most common tumor types were colorectal (17.2%), ovarian (8.0%), and non-small cell lung (6.9%) cancers. Patients received a median three (range 1-9) prior therapies, including immunotherapy in 24 patients (27.6%). Maximum tolerated dose was not reached; one patient (1.1%) receiving 350 mg dose reported dose-limiting toxicity of grade 3 colitis. Treatment-related adverse events were reported in 45 patients (51.7%), with fatigue (16 (18.4%)), rash (6 (6.9%)), and diarrhea (6 (6.9%)) being most frequent. One patient (1.1%) with metastatic gallbladder cancer achieved a partial response (duration of 6.3 months), and 23 patients (26.4%) achieved stable disease (lasting >6 months in one patient). OX40 receptor occupancy was maintained over 90% among all patients receiving doses of ≥200 mg, while no treatment-emergent antidrug antibodies were detected across all dose levels. Pharmacodynamic results demonstrated that treatment with INCAGN01949 did not enhance proliferation or activation of T cells in peripheral blood or reduce circulating Tregs, and analyses of tumor biopsies did not demonstrate any consistent increase in effector T-cell infiltration or function, or decrease in infiltrating Tregs. CONCLUSION: No safety concerns were observed with INCAGN01949 monotherapy in patients with metastatic or advanced solid tumors. However, tumor responses and pharmacodynamic effects on T cells in peripheral blood and post-therapy tumor biopsies were limited. Studies evaluating INCAGN01949 in combination with other therapies are needed to further evaluate the potential of OX40 agonism as a therapeutic approach in patients with advanced solid tumors. TRIAL REGISTRATION NUMBER: NCT02923349.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Dose Máxima Tolerável , Receptores OX40RESUMO
Immune checkpoint inhibitors demonstrate clinical activity in many tumor types, however, only a fraction of patients benefit. Combining CD137 agonists with these inhibitors increases anti-tumor activity preclinically, but attempts to translate these observations to the clinic have been hampered by systemic toxicity. Here we describe a human CD137xPD-L1 bispecific antibody, MCLA-145, identified through functional screening of agonist- and immune checkpoint inhibitor arm combinations. MCLA-145 potently activates T cells at sub-nanomolar concentrations, even under suppressive conditions, and enhances T cell priming, differentiation and memory recall responses. In vivo, MCLA-145 anti-tumor activity is superior to immune checkpoint inhibitor comparators and linked to recruitment and intra-tumor expansion of CD8 + T cells. No graft-versus-host-disease is observed in contrast to other antibodies inhibiting the PD-1 and PD-L1 pathway. Non-human primates treated with 100 mg/kg/week of MCLA-145 show no adverse effects. The conditional activation of CD137 signaling by MCLA-145, triggered by neighboring cells expressing >5000 copies of PD-L1, may provide both safety and potency advantages.
Assuntos
Ligante 4-1BB/agonistas , Anticorpos Biespecíficos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/farmacologia , Ligante 4-1BB/imunologia , Animais , Anticorpos Biespecíficos/imunologia , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/imunologia , Epitopos , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Tolerância Imunológica/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Imunoterapia , Ativação Linfocitária/efeitos dos fármacosRESUMO
Decision making in immuno-oncology is pivotal to adapt therapy to the tumor microenvironment (TME) of the patient among the numerous options of monoclonal antibodies or small molecules. Predicting the best combinatorial regimen remains an unmet medical need. Here, we report a multiplex functional and dynamic immuno-assay based on the capacity of the TME to respond to ex vivo stimulation with twelve immunomodulators including immune checkpoint inhibitors (ICI) in 43 human primary tumors. This "in sitro" (in situ/in vitro) assay has the potential to predict unresponsiveness to anti-PD-1 mAbs, and to detect the most appropriate and personalized combinatorial regimen. Prospective clinical trials are awaited to validate this in sitro assay.
Assuntos
Imunoterapia , Neoplasias , Humanos , Oncologia , Neoplasias/terapia , Estudos Prospectivos , Microambiente TumoralRESUMO
Buffalo/Mna rats spontaneously develop FSGS and nephrotic syndrome as a result of an immune disorder. Similar to some humans with FSGS, the disease recurs after renal transplantation, suggesting the involvement of a circulating factor. Here, we tested the effect of several immunosuppressive treatments on these rats. Although corticosteroids, cyclosporin A, and anti-T cell receptor treatment reduced proteinuria, only the deoxyspergualin derivative LF15-0195 led to a rapid and complete normalization of proteinuria. Furthermore, this compound led to the regression of renal lesions during both the initial disease and posttransplantation recurrence. The frequency of splenic and peripheral CD4+CD25+FoxP3+ T lymphocytes significantly increased with remission. Moreover, the transfer of purified LF15-0195-induced CD4+CD25+ T cells to irradiated Buff/Mna rats significantly reduced their proteinuria compared with the transfer of untreated control cells, suggesting that LF15-0195 induces regulatory T cells that are able to induce regression of rat nephropathy. These data suggest that idiopathic nephrotic syndrome/FSGS disease can be regulated by cellular transfer, but how this regulation leads to the reorganization of the podocyte cytoskeleton remains to be determined.
Assuntos
Imunossupressores/uso terapêutico , Síndrome Nefrótica/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Anticorpos Monoclonais/uso terapêutico , Citocinas/genética , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Glomerulosclerose Segmentar e Focal/imunologia , Guanidinas/uso terapêutico , Transplante de Rim/efeitos adversos , Masculino , NF-kappa B/fisiologia , Síndrome Nefrótica/imunologia , Ratos , Receptores de Antígenos de Linfócitos T/fisiologia , Recidiva , Linfócitos T Reguladores/efeitos dos fármacosRESUMO
Agonists of the co-stimulatory molecule OX40 (CD134) are in clinical assessment alone and in combination with other immunotherapies. Recent pre-clinical studies have suggested that concurrent administration of OX40 agonists with anti-PD1 therapy is detrimental to the efficacy of such combinations and maximal efficacy may require sequential administration of the OX40 agonist followed by anti-PD1 therapy. In this report, we detail two patients with advanced ovarian carcinoma were treated with INCAGN01949, an agonistic OX40 Ab, as part of a clinical trial until disease progression. Both patients then received the combination of ipilimumab and nivolumab and experienced unusually deep and durable responses. These cases support the hypothesis raised in pre-clinical studies and highlight the potential relevance of sequence in combinational immunotherapy.
RESUMO
Here, we report that functional heterogeneity of macrophages in cancer could be determined by the nature of their precursors: monocytes (Mons) and monocytic myeloid-derived suppressor cells (M-MDSCs). Macrophages that are differentiated from M-MDSCs, but not from Mons, are immune suppressive, with a genomic profile matching that of M-MDSCs. Immune-suppressive activity of M-MDSC-derived macrophages is dependent on the persistent expression of S100A9 protein in these cells. S100A9 also promotes M2 polarization of macrophages. Tissue-resident- and Mon-derived macrophages lack expression of this protein. S100A9-dependent immune-suppressive activity of macrophages involves transcription factor C/EBPß. The presence of S100A9-positive macrophages in tumor tissues is associated with shorter survival in patients with head and neck cancer and poor response to PD-1 antibody treatment in patients with metastatic melanoma. Thus, this study reveals the pathway of the development of immune-suppressive macrophages and suggests an approach to their selective targeting.
Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Calgranulina A/fisiologia , Calgranulina B/fisiologia , Terapia de Imunossupressão , Macrófagos/metabolismo , Monócitos/metabolismo , Células Supressoras Mieloides/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise em Microsséries , Pessoa de Meia-Idade , Células Supressoras Mieloides/imunologia , Microambiente TumoralRESUMO
Jellyfish (medusae) are a distinctive life-cycle stage of medusozoan cnidarians. They are major marine predators, with integrated neurosensory, muscular and organ systems. The genetic foundations of this complex form are largely unknown. We report the draft genome of the hydrozoan jellyfish Clytia hemisphaerica and use multiple transcriptomes to determine gene use across life-cycle stages. Medusa, planula larva and polyp are each characterized by distinct transcriptome signatures reflecting abrupt life-cycle transitions and all deploy a mixture of phylogenetically old and new genes. Medusa-specific transcription factors, including many with bilaterian orthologues, associate with diverse neurosensory structures. Compared to Clytia, the polyp-only hydrozoan Hydra has lost many of the medusa-expressed transcription factors, despite similar overall rates of gene content evolution and sequence evolution. Absence of expression and gene loss among Clytia orthologues of genes patterning the anthozoan aboral pole, secondary axis and endomesoderm support simplification of planulae and polyps in Hydrozoa, including loss of bilateral symmetry. Consequently, although the polyp and planula are generally considered the ancestral cnidarian forms, in Clytia the medusa maximally deploys the ancestral cnidarian-bilaterian transcription factor gene complement.
Assuntos
Hidrozoários , Animais , Evolução Molecular , GenomaRESUMO
We have identified a precursor that differentiates into granulocytes in vitro and in vivo yet belongs to the monocytic lineage. We have termed these cells monocyte-like precursors of granulocytes (MLPGs). Under steady state conditions, MLPGs were absent in the spleen and barely detectable in the bone marrow (BM). In contrast, these cells significantly expanded in tumor-bearing mice and differentiated to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Selective depletion of monocytic cells had no effect on the number of granulocytes in naive mice but decreased the population of PMN-MDSCs in tumor-bearing mice by 50%. The expansion of MLPGs was found to be controlled by the down-regulation of Rb1, but not IRF8, which is known to regulate the expansion of PMN-MDSCs from classic granulocyte precursors. In cancer patients, putative MLPGs were found within the population of CXCR1+CD15-CD14+HLA-DR-/lo monocytic cells. These findings describe a mechanism of abnormal myelopoiesis in cancer and suggest potential new approaches for selective targeting of MDSCs.
Assuntos
Monócitos/patologia , Células Supressoras Mieloides/patologia , Neoplasias/patologia , Neutrófilos/patologia , Adulto , Idoso , Animais , Diferenciação Celular , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteínas de Ligação a Retinoblastoma/metabolismoRESUMO
Purpose: Myeloid-derived suppressor cells (MDSC) are one of the major contributors to immune suppression in cancer. We recently have demonstrated in preclinical study that MDSCs are sensitive to TRAIL receptor 2 (TRAIL-R2) agonist. The goal of this study was to clinically test the hypothesis that targeting TRAIL-R2 can selectively eliminate MDSCs.Experimental Design: The TRAIL-R2 agonistic antibody (DS-8273a) has been tested in 16 patients with advanced cancers enrolled in a phase I trial. The antibody (24 mg/kg) was administered intravenously once every 3 weeks till disease progression, unacceptable toxicities, or withdrawal of consent. The safety and the presence of various populations of myeloid and lymphoid cells in peripheral blood and tumor tissues were evaluated.Results: The treatment was well tolerated with only mild to moderate adverse events attributable to the study drug. Treatment with DS-8273a resulted in reduction of the elevated numbers of MDSCs in the peripheral blood of most patients to the levels observed in healthy volunteers. However, in several patients, MDSCs rebounded back to the pretreatment level by day 42. In contrast, DS-8273a did not affect the number of neutrophils, monocytes, and other populations of myeloid and lymphoid cells. Decrease in MDSCs inversely correlated with the length of progression-free survival. In tumors, DS-8273a treatment resulted in a decrease of MDSCs in 50% of the patients who were able to provide pre- and on-treatment biopsies.Conclusions: Targeting TRAIL-R2 resulted in elimination of different populations of MDSCs without affecting mature myeloid or lymphoid cells. These data support the use of this antibody in combination immmunotherapy of cancer. Clin Cancer Res; 23(12); 2942-50. ©2016 AACR.
Assuntos
Imunoterapia , Células Supressoras Mieloides/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Intervalo Livre de Doença , Humanos , Terapia de Imunossupressão , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Pessoa de Meia-Idade , Monócitos/imunologia , Células Mieloides/imunologia , Células Supressoras Mieloides/imunologia , Neoplasias/imunologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/agonistasRESUMO
Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects.
Assuntos
Fibroblastos Associados a Câncer/metabolismo , Monócitos/metabolismo , Células Supressoras Mieloides/metabolismo , Neoplasias Experimentais/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Animais , Fibroblastos Associados a Câncer/efeitos dos fármacos , Linhagem Celular Tumoral , Granulócitos/metabolismo , Histona Desacetilase 2 , Humanos , Imidazóis/farmacologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/metabolismo , Carga Tumoral/efeitos dos fármacosRESUMO
Multiple myeloma (MM) is an incurable cancer of plasma cells localized preferentially in the bone marrow (BM). Resistance to chemotherapy represents one of the main challenges in MM management. BM microenvironment is known to play a critical role in protection of MM cells from chemotherapeutics; however, mechanisms responsible for this effect are largely unknown. Development of MM is associated with accumulation of myeloid-derived suppressor cells (MDSCs) mostly represented by pathologically activated relatively immature polymorphonuclear neutrophils (PMN-MDSCs). Here, we investigated whether PMN-MDSCs are responsible for BM microenvironment-mediated MM chemoresistance. Using in vivo mouse models allowing manipulation of myeloid cell number, we demonstrated a critical role for myeloid cells in MM growth and chemoresistance. PMN-MDSCs isolated from MM-bearing host are immunosuppressive and thus, functionally distinct from their counterpart in tumor-free host neutrophils. We found, however, that both PMN-MDSCs and neutrophils equally promote MM survival from doxorubicin and melphalan and that this effect is mediated by soluble factors rather than direct cell-cell contact. Our data indicate that targeting PMN-MDSCs would enhance chemotherapy efficacy in MM.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Antineoplásicos Alquilantes/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Melfalan/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Células Mieloides/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Linhagem da Célula , Técnicas de Cocultura , Modelos Animais de Doenças , Humanos , Camundongos Endogâmicos C57BL , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Células Mieloides/metabolismo , Células Mieloides/patologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Comunicação Parácrina , Fenótipo , Fatores de Tempo , Células Tumorais Cultivadas , Microambiente TumoralRESUMO
Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are important regulators of immune responses in cancer and have been directly implicated in promotion of tumor progression. However, the heterogeneity of these cells and lack of distinct markers hampers the progress in understanding of the biology and clinical importance of these cells. Using partial enrichment of PMN-MDSC with gradient centrifugation we determined that low density PMN-MDSC and high density neutrophils from the same cancer patients had a distinct gene profile. Most prominent changes were observed in the expression of genes associated with endoplasmic reticulum (ER) stress. Surprisingly, low-density lipoprotein (LDL) was one of the most increased regulators and its receptor oxidized LDL receptor 1 OLR1 was one of the most overexpressed genes in PMN-MDSC. Lectin-type oxidized LDL receptor 1 (LOX-1) encoded by OLR1 was practically undetectable in neutrophils in peripheral blood of healthy donors, whereas 5-15% of total neutrophils in cancer patients and 15-50% of neutrophils in tumor tissues were LOX-1+. In contrast to their LOX-1- counterparts, LOX-1+ neutrophils had gene signature, potent immune suppressive activity, up-regulation of ER stress, and other biochemical characteristics of PMN-MDSC. Moreover, induction of ER stress in neutrophils from healthy donors up-regulated LOX-1 expression and converted these cells to suppressive PMN-MDSC. Thus, we identified a specific marker of human PMN-MDSC associated with ER stress and lipid metabolism, which provides new insight to the biology and potential therapeutic targeting of these cells.