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1.
Immunol Rev ; 314(1): 13-35, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36527200

RESUMO

Neutrophils sense microbes and host inflammatory mediators, and traffic to sites of infection where they direct a broad armamentarium of antimicrobial products against pathogens. Neutrophils are also activated by damage-associated molecular patterns (DAMPs), which are products of cellular injury that stimulate the innate immune system through pathways that are similar to those activated by microbes. Neutrophils and platelets become activated by injury, and cluster and cross-signal to each other with the cumulative effect of driving antimicrobial defense and hemostasis. In addition, neutrophil extracellular traps are extracellular chromatin and granular constituents that are generated in response to microbial and damage motifs and are pro-thrombotic and injurious. Although neutrophils can worsen tissue injury, neutrophils may also have a role in facilitating wound repair following injury. A central theme of this review relates to how critical functions of neutrophils that evolved to respond to infection and damage modulate the tumor microenvironment (TME) in ways that can promote or limit tumor progression. Neutrophils are reprogrammed by the TME, and, in turn, can cross-signal to tumor cells and reshape the immune landscape of tumors. Importantly, promising new therapeutic strategies have been developed to target neutrophil recruitment and function to make cancer immunotherapy more effective.


Assuntos
Armadilhas Extracelulares , Neutrófilos , Humanos , Plaquetas/metabolismo , Plaquetas/patologia , Células Endoteliais , Inflamação , Linfócitos T , Armadilhas Extracelulares/metabolismo
2.
Cancer Immunol Immunother ; 71(10): 2355-2369, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35166871

RESUMO

The ovarian tumor microenvironment (TME) is characterized by the accumulation of immunosuppressive tumor-associated macrophages (TAMs) and granulocytic cells. Very small size particles (VSSP), comprised of the ganglioside NAcGM3 and Neisseria meningitidis derived outer membrane vesicles, is being developed as a nanoparticulated modulator of innate immunity. Prior studies have shown that VSSP enhanced antigen-specific cytotoxic T cell responses and reduced the suppressive phenotype of splenic granulocytic cells in tumor-bearing mice. Here, we hypothesized that intraperitoneal VSSP would modify myeloid cell accumulation and phenotypes in the ovarian TME and abrogate suppressor function of TAMs and tumor-associated granulocytic cells. In the ID8 syngeneic model of epithelial ovarian cancer, VSSP reduced peritoneal TAMs and induced M1-like polarization in TAMs. In addition, VSSP stimulated peritoneal inflammation characterized by increased granulocytes and monocytes, including inflammatory monocytic cells. VSSP treatment resulted in peritoneal TAMs and granulocytic cells being less suppressive of ex vivo stimulated CD8+ T cell responses. VSSP alone and combined with anti-PD-1 modestly but significantly prolonged survival in tumor-bearing mice. In addition, ex vivo treatment with VSSP induced M1-like polarization in TAMs from patients with metastatic ovarian cancer and variably abrogated their suppressor phenotype. VSSP treatment also partially abrogated the induction of suppressor function in healthy donor neutrophils exposed to ascites supernatants from patients with ovarian cancer. Together, these results point to VSSP reprogramming myeloid responses resulting in abrogation of suppressive pathways and raise the potential for administration of VSSP into the TME to enhance anti-tumor immunity.


Assuntos
Neoplasias Ovarianas , Macrófagos Associados a Tumor , Animais , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides , Microambiente Tumoral
3.
Br J Cancer ; 120(2): 207-217, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30518816

RESUMO

BACKGROUND: Advanced cancer causes necrosis and releases damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs activate neutrophils, including generation of neutrophil extracellular traps (NETs), which are injurious, thrombogenic, and implicated in metastasis. We hypothesised that extracellular mitochondrial DNA (mtDNA) in ascites from patients with epithelial ovarian cancer (EOC) would correlate with worse outcomes. METHODS: Banked ascites supernatants from patients with newly diagnosed advanced EOC were analysed for mtDNA, neutrophil elastase, and activation of healthy donor neutrophils and platelets. TCGA was mined for expression of SELP and ELANE. RESULTS: The highest quartile of ascites mtDNA correlated with reduced progression-free survival (PFS) and a higher likelihood of disease progression within 12-months following primary surgery (n = 68, log-rank, p = 0.0178). NETs were detected in resected tumours. Ascites supernatants chemoattracted neutrophils, induced NETs, and activated platelets. Ascites exposure rendered neutrophils suppressive, based on abrogation of ex vivo stimulated T cell proliferation. Increased SELP mRNA expression correlated with worse overall survival (n = 302, Cox model, p = 0.02). CONCLUSION: In this single-centre retrospective analysis, ascites mtDNA correlated with worse PFS in advanced EOC. Mitochondrial and other DAMPs in ascites may activate neutrophil and platelet responses that facilitate metastasis and obstruct anti-tumour immunity. These pathways are potential prognostic markers and therapeutic targets.


Assuntos
Alarminas/genética , Carcinoma Epitelial do Ovário/genética , DNA Mitocondrial/genética , Armadilhas Extracelulares/genética , Idoso , Ascite/genética , Ascite/patologia , Plaquetas/metabolismo , Carcinoma Epitelial do Ovário/patologia , Armadilhas Extracelulares/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Elastase de Leucócito/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neutrófilos/metabolismo , Neutrófilos/patologia , Intervalo Livre de Progressão , Microambiente Tumoral/genética
4.
Cell Mol Immunol ; 21(3): 260-274, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38233562

RESUMO

Metabolic flexibility has emerged as a critical determinant of CD8+ T-cell antitumor activity, yet the mechanisms driving the metabolic flexibility of T cells have not been determined. In this study, we investigated the influence of the nuclear cap-binding complex (CBC) adaptor protein ARS2 on mature T cells. In doing so, we discovered a novel signaling axis that endows activated CD8+ T cells with flexibility of glucose catabolism. ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events. Among these effects, the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2, a key determinant of CD8+ T-cell glucose utilization, interferon gamma production, and antitumor effector function. Importantly, PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation, revealing a novel means by which costimulation reprograms glucose metabolism in CD8+ T cells.


Assuntos
Processamento Alternativo , Antígenos CD28 , Antígenos CD28/metabolismo , Processamento Alternativo/genética , Fosfatidilinositol 3-Quinases/metabolismo , Linfócitos T CD8-Positivos , Glucose/metabolismo
5.
J Trauma Acute Care Surg ; 94(2): 187-196, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36694330

RESUMO

INTRODUCTION: Multiple large clinical trauma trials have documented an increased susceptibility to infection after injury. Although neutrophils (polymorphonuclear leukocytes [PMNs]) were historically considered a homogeneous cell type, we hypothesized that injury could alter neutrophil heterogeneity and predispose to dysfunction. To explore whether trauma modifies PMN heterogeneity, we performed an observational mass-spectrometry-based cytometry study on total leukocytes and low-density PMNs found in the peripheral blood mononuclear cell fraction of leukocytes from healthy controls and trauma patients. METHODS: A total of 74 samples from 12 trauma patients, each sampled at 1 or more time points, and matched controls were fractionated and profiled by mass-spectrometry-based cytometry using a panel of 44 distinct markers. After deconvolution and conservative gating on neutrophils, data were analyzed using Seurat, followed by clustering of principal components. RESULTS: Eleven distinct neutrophil populations were resolved in control and trauma neutrophils based on differential protein surface marker expression. Trauma markedly altered the basal heterogeneity of neutrophil subgroups seen in the control samples, with loss of a dominant population of resting neutrophils marked by high expression of C3AR and low levels of CD63, CD64, and CD177 (cluster 1), and expansion of two alternative neutrophil populations, one of which is marked by high expression of CD177 with suppression of CD10, CD16, C3AR, CD63, and CD64 (cluster 6). Remarkably, following trauma, a substantially larger percentage of neutrophils sediment in the monocyte fraction. These low-density neutrophils bear markers of functional exhaustion and form a unique trauma-induced population (cluster 9) with markedly upregulated expression of active surface adhesion molecules (activated CD11b/CD18), with suppression of nearly all other surface markers, including receptors for formyl peptides, leukotrienes, chemokines, and complement. CONCLUSION: Circulating neutrophils demonstrate considerable evidence of functional heterogeneity that is markedly altered by trauma. Trauma induces evolution of a novel, exhausted, low-density neutrophil population with immunosuppressive features.


Assuntos
Antígenos CD18 , Neutrófilos , Humanos , Neutrófilos/metabolismo , Antígenos CD18/metabolismo , Leucócitos Mononucleares/metabolismo , Leucócitos/metabolismo , Quimiocinas
6.
Mol Cell Oncol ; 9(1): 2039038, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35402699

RESUMO

Inducing immunogenic tumor cell death to stimulate the response to immune checkpoint blockade has not yet been effectively translated into clinical practice. We recently discovered that stressed/injured but still viable tumor cells are critical for T-cell priming and substantially improve responses to systemic anti-PD1/CTLA4. Therapeutic tumor cell injury, rather than complete killing, in the tumor microenvironment may enhance efficacy of immunotherapy in various cancers.

7.
Commun Biol ; 4(1): 102, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33483601

RESUMO

Pro-inflammatory M1 macrophage polarization is associated with microbicidal and antitumor responses. We recently described APOBEC3A-mediated cytosine-to-uracil (C > U) RNA editing during M1 polarization. However, the functional significance of this editing is unknown. Here we find that APOBEC3A-mediated cellular RNA editing can also be induced by influenza or Maraba virus infections in normal human macrophages, and by interferons in tumor-associated macrophages. Gene knockdown and RNA_Seq analyses show that APOBEC3A mediates C>U RNA editing of 209 exonic/UTR sites in 203 genes during M1 polarization. The highest level of nonsynonymous RNA editing alters a highly-conserved amino acid in THOC5, which encodes a nuclear mRNA export protein implicated in M-CSF-driven macrophage differentiation. Knockdown of APOBEC3A reduces IL6, IL23A and IL12B gene expression, CD86 surface protein expression, and TNF-α, IL-1ß and IL-6 cytokine secretion, and increases glycolysis. These results show a key role of APOBEC3A cytidine deaminase in transcriptomic and functional polarization of M1 macrophages.


Assuntos
Citidina Desaminase/metabolismo , Macrófagos/metabolismo , Proteínas Nucleares/metabolismo , Proteínas/metabolismo , Edição de RNA , Humanos , Cultura Primária de Células
8.
Cancer Immunol Res ; 9(7): 790-810, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33990375

RESUMO

T-cell activation and expansion in the tumor microenvironment (TME) are critical for antitumor immunity. Neutrophils in the TME acquire a complement-dependent T-cell suppressor phenotype that is characterized by inhibition of T-cell proliferation and activation through mechanisms distinct from those of myeloid-derived suppressor cells. In this study, we used ascites fluid supernatants (ASC) from patients with ovarian cancer as an authentic component of the TME to evaluate the effects of ASC on neutrophil function and mechanisms for neutrophil-driven immune suppression. ASC prolonged neutrophil life span, decreased neutrophil density, and induced nuclear hypersegmentation. Mass cytometry analysis showed that ASC induced 15 distinct neutrophil clusters. ASC stimulated complement deposition and signaling in neutrophils, resulting in surface mobilization of granule constituents, including NADPH oxidase. NADPH oxidase activation and phosphatidylserine signaling were required for neutrophil suppressor function, although we did not observe a direct role of extracellular reactive oxygen species in inhibiting T-cell proliferation. Postoperative surgical drainage fluid also induced a complement-dependent neutrophil suppressor phenotype, pointing to this effect as a general response to injury. Like circulating lymphocytes, ASC-activated neutrophils caused complement-dependent suppression of tumor-associated lymphocytes. ASC-activated neutrophils adhered to T cells and caused trogocytosis of T-cell membranes. These injury and signaling cues resulted in T-cell immunoparalysis characterized by impaired NFAT translocation, IL2 production, glucose uptake, mitochondrial function, and mTOR activation. Our results demonstrate that complement-dependent priming of neutrophil effector functions in the TME induces a T-cell nonresponsiveness distinct from established checkpoint pathways and identify targets for immunotherapy.See related Spotlight by Cassatella, p. 725.


Assuntos
Neutrófilos/imunologia , Neoplasias Ovarianas/imunologia , Linfócitos T/imunologia , Trogocitose/imunologia , Evasão Tumoral , Adulto , Células Cultivadas , Feminino , Humanos , Ativação Linfocitária , Pessoa de Meia-Idade , Ativação de Neutrófilo , Neutrófilos/metabolismo , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Cultura Primária de Células , Microambiente Tumoral/imunologia , Adulto Jovem
9.
Cancer Immunol Res ; 8(6): 819-828, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32238380

RESUMO

Myeloid derived suppressor cells (MDSC) are a heterogeneous group of immature cells that accumulate in the peripheral blood and tumor microenvironment and are barriers to cancer therapy. MDSCs serve as prognostic biomarkers and are targets for therapy. On the basis of surface markers, three subsets of MDSCs have been defined in humans: granulocytic, monocytic, and early stage (e-MDSC). The markers attributed to e-MDSCs overlap with those of basophils, which are rare circulating myeloid cells with unrecognized roles in cancer. Thus, we asked whether e-MDSCs in circulation and the tumor microenvironment include basophils. On average, 58% of cells with e-MDSC surface markers in blood and 36% in ascites from patients with ovarian cancer were basophils based on CD123high expression and cytology, whereas cells with immature features were rare. Circulating and ascites basophils did not suppress proliferation of stimulated T cells, a key feature of MDSCs. Increased accumulation of basophils and basogranulin, a marker of basophil degranulation, were observed in ascites compared to serum in patients with newly diagnosed ovarian cancer. Basophils recruited to the tumor microenvironment may exacerbate fluid accumulation by their release of proinflammatory granular constituents that promote vascular leakage. No significant correlation was observed between peripheral basophil counts and survival in patients with ovarian cancer. Our results suggest that studies in which e-MDSCs were defined solely by surface markers should be reevaluated to exclude basophils. Both immaturity and suppression are criteria to define e-MDSCs in future studies.


Assuntos
Ascite/patologia , Basófilos/patologia , Biomarcadores Tumorais/sangue , Leucócitos Mononucleares/patologia , Células Supressoras Mieloides/patologia , Neoplasias Ovarianas/patologia , Microambiente Tumoral , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/cirurgia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida , Células Tumorais Cultivadas
10.
JCI Insight ; 4(5)2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30730851

RESUMO

Epithelial ovarian cancer (EOC) often presents with metastases and ascites. Granulocytic myeloid-derived suppressor cells are an immature population that impairs antitumor immunity. Since suppressive granulocytes in the ascites of patients with newly diagnosed EOC were morphologically mature, we hypothesized that PMN were rendered suppressive in the tumor microenvironment (TME). Circulating PMN from patients were not suppressive but acquired a suppressor phenotype (defined as ≥1 log10 reduction of anti-CD3/CD28-stimulated T cell proliferation) after ascites supernatant exposure. Ascites supernatants (20 of 31 supernatants) recapitulated the suppressor phenotype in PMN from healthy donors. T cell proliferation was restored with ascites removal and restimulation. PMN suppressors also inhibited T cell activation and cytokine production. PMN suppressors completely suppressed proliferation in naive, central memory, and effector memory T cells and in engineered tumor antigen-specific cytotoxic T lymphocytes, while antigen-specific cell lysis was unaffected. Inhibition of complement C3 activation and PMN effector functions, including CR3 signaling, protein synthesis, and vesicular trafficking, abrogated the PMN suppressor phenotype. Moreover, malignant effusions from patients with various metastatic cancers also induced the C3-dependent PMN suppressor phenotype. These results point to PMN impairing T cell expansion and activation in the TME and the potential for complement inhibition to abrogate this barrier to antitumor immunity.


Assuntos
Imunidade , Neutrófilos/imunologia , Neoplasias Ovarianas/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Idoso , Antígenos CD28 , Proliferação de Células , Complemento C3 , Citocinas , Feminino , Granulócitos , Humanos , Ativação Linfocitária/imunologia , Muromonab-CD3 , Células Supressoras Mieloides/imunologia , Neoplasias Ovarianas/patologia
11.
Toxicol Sci ; 143(2): 418-29, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25433234

RESUMO

The herbicide atrazine (2-chloro-4-[ethylamino]-6-[isopropylamino]-s-triazine) is the most common water contaminant in the United States. Atrazine is a phosphodiesterase inhibitor and is classified as an estrogen disrupting compound because it elevates estrogen levels via induction of the enzyme aromatase. Previous studies have shown that atrazine exposure alters the function of innate immune cells such as NK cells, DC, mast cells, and macrophages. In this study we have examined the impact of in vitro atrazine exposure on the activation, proliferation, and effector cytokine production by primary murine CD4(+) T lymphocytes. We found that atrazine exposure significantly inhibited CD4(+) T cell proliferation and accumulation as well as the expression of the activation markers CD25 and CD69 in a dose-dependent manner. Interestingly, the effects were more pronounced in cells from male animals. These effects were partially mimicked by pharmacological reagents that elevate intracellular cAMP levels and addition of exogenous rmIL-2 further inhibited proliferation and CD25 expression. Consistent with these findings, atrazine exposure during T cell activation resulted in a 2- to 5-fold increase in the frequency of Foxp3(+) CD4(+) T cells.


Assuntos
Atrazina/toxicidade , Proliferação de Células/efeitos dos fármacos , Citocinas/biossíntese , Fatores de Transcrição Forkhead/genética , Herbicidas/toxicidade , Ativação Linfocitária/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Técnicas de Cultura de Células , Células Cultivadas , AMP Cíclico/metabolismo , Citometria de Fluxo , Técnicas de Introdução de Genes , Interleucina-2/farmacologia , Masculino , Dose Máxima Tolerável , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Baço/citologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
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