RESUMO
Clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to immune checkpoint blockade (ICB) in several solid tumor types independent of microsatellite instability. We show that ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypes observed in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolytic activity. ARID1A-deficient cancers upregulated an interferon (IFN) gene expression signature, the ARID1A-IFN signature, associated with increased R-loops and cytosolic single-stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B, or cytosolic DNase, TREX1, in ARID1A-deficient cells prevented cytosolic ssDNA accumulation and ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumor immunity were driven by STING-dependent type I IFN signaling, which was required for improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings define a molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers.
Assuntos
Linfócitos T CD8-Positivos , Proteínas de Ligação a DNA , Interferon Tipo I , Proteínas de Membrana , Neoplasias , Transdução de Sinais , Fatores de Transcrição , Animais , Humanos , Camundongos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Exodesoxirribonucleases/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Mutação , Neoplasias/imunologia , Neoplasias/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Fatores de Transcrição/metabolismo , Masculino , Quimiocinas/genética , Quimiocinas/metabolismoRESUMO
The continuous migration of immune cells between lymphoid and nonlymphoid organs is a key feature of the immune system, facilitating the distribution of effector cells within nearly all compartments of the body. Furthermore, reaching their correct position within primary, secondary, or tertiary lymphoid organs is a prerequisite to ensure immune cells' unimpaired differentiation, maturation, and selection, as well as their activation or functional silencing. The superfamilies of chemokines and chemokine receptors are of major importance in guiding immune cells to and within lymphoid and nonlymphoid tissues. In this review we focus on the role of the chemokine system in the migration dynamics of immune cells within lymphoid organs at the steady state and on how these dynamics are affected by infectious and inflammatory processes.
Assuntos
Quimiocinas/imunologia , Sistema Imunitário , Infecções/imunologia , Inflamação/imunologia , Linfócitos/imunologia , Tecido Linfoide/imunologia , Receptores de Quimiocinas/imunologia , Animais , Comunicação Celular , Movimento Celular , Humanos , Ativação LinfocitáriaRESUMO
Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces cytokines/chemokines to activate resistance mechanisms. Here, we show that, in contrast to most pathogen-induced cytokines, interleukin-24 (IL-24) is predominately induced by barrier epithelial progenitors after tissue injury and is independent of microbiome or adaptive immunity. Moreover, Il24 ablation in mice impedes not only epidermal proliferation and re-epithelialization but also capillary and fibroblast regeneration within the dermal wound bed. Conversely, ectopic IL-24 induction in the homeostatic epidermis triggers global epithelial-mesenchymal tissue repair responses. Mechanistically, Il24 expression depends upon both epithelial IL24-receptor/STAT3 signaling and hypoxia-stabilized HIF1α, which converge following injury to trigger autocrine and paracrine signaling involving IL-24-mediated receptor signaling and metabolic regulation. Thus, parallel to innate immune sensing of pathogens to resolve infections, epithelial stem cells sense injury signals to orchestrate IL-24-mediated tissue repair.
Assuntos
Citocinas , Ferimentos e Lesões , Animais , Camundongos , Imunidade Adaptativa , Quimiocinas , Epiderme , Imunidade Inata , Ferimentos e Lesões/imunologiaRESUMO
The organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially localized multicellular 'immunity hubs' defined by expression of the T cell-attracting chemokines CXCL10/CXCL11 and abundant T cells. Here, we examined immunity hubs in human pre-immunotherapy lung cancer specimens and found an association with beneficial response to PD-1 blockade. Critically, we discovered the stem-immunity hub, a subtype of immunity hub strongly associated with favorable PD-1-blockade outcome. This hub is distinct from mature tertiary lymphoid structures and is enriched for stem-like TCF7+PD-1+CD8+ T cells, activated CCR7+LAMP3+ dendritic cells and CCL19+ fibroblasts as well as chemokines that organize these cells. Within the stem-immunity hub, we find preferential interactions between CXCL10+ macrophages and TCF7-CD8+ T cells as well as between mature regulatory dendritic cells and TCF7+CD4+ and regulatory T cells. These results provide a picture of the spatial organization of the human intratumoral immune response and its relevance to patient immunotherapy outcomes.
Assuntos
Neoplasias Pulmonares , Humanos , Linfócitos T CD8-Positivos , Receptor de Morte Celular Programada 1 , Quimiocinas/metabolismo , Imunoterapia/métodos , Microambiente TumoralRESUMO
Lung-resident macrophages, which include alveolar macrophages and interstitial macrophages (IMs), exhibit a high degree of diversity, generally attributed to different activation states, and often complicated by the influx of monocytes into the pool of tissue-resident macrophages. To gain a deeper insight into the functional diversity of IMs, here we perform comprehensive transcriptional profiling of resident IMs and reveal ten distinct chemokine-expressing IM subsets at steady state and during inflammation. Similar IM subsets that exhibited coordinated chemokine signatures and differentially expressed genes were observed across various tissues and species, indicating conserved specialized functional roles. Other macrophage types shared specific IM chemokine profiles, while also presenting their own unique chemokine signatures. Depletion of CD206hi IMs in Pf4creR26EYFP+DTR and Pf4creR26EYFPCx3cr1DTR mice led to diminished inflammatory cell recruitment, reduced tertiary lymphoid structure formation and fewer germinal center B cells in models of allergen- and infection-driven inflammation. These observations highlight the specialized roles of IMs, defined by their coordinated chemokine production, in regulating immune cell influx and organizing tertiary lymphoid tissue architecture.
Assuntos
Quimiocinas , Macrófagos , Animais , Camundongos , Quimiocinas/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Pulmão/imunologia , Camundongos Endogâmicos C57BL , Inflamação/imunologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Especificidade de Órgãos/imunologia , Perfilação da Expressão Gênica , Camundongos Transgênicos , Estruturas Linfoides Terciárias/imunologia , TranscriptomaRESUMO
Sepsis induces immune alterations, which last for months after the resolution of illness. The effect of this immunological reprogramming on the risk of developing cancer is unclear. Here we use a national claims database to show that sepsis survivors had a lower cumulative incidence of cancers than matched nonsevere infection survivors. We identify a chemokine network released from sepsis-trained resident macrophages that triggers tissue residency of T cells via CCR2 and CXCR6 stimulations as the immune mechanism responsible for this decreased risk of de novo tumor development after sepsis cure. While nonseptic inflammation does not provoke this network, laminarin injection could therapeutically reproduce the protective sepsis effect. This chemokine network and CXCR6 tissue-resident T cell accumulation were detected in humans with sepsis and were associated with prolonged survival in humans with cancer. These findings identify a therapeutically relevant antitumor consequence of sepsis-induced trained immunity.
Assuntos
Macrófagos , Neoplasias , Sepse , Humanos , Sepse/imunologia , Macrófagos/imunologia , Feminino , Neoplasias/imunologia , Neoplasias/terapia , Masculino , Receptores CXCR6/metabolismo , Animais , Linfócitos T/imunologia , Receptores CCR2/metabolismo , Pessoa de Meia-Idade , Camundongos , Idoso , Quimiocinas/metabolismo , AdultoRESUMO
Chemokines are chemotactic cytokines that control the migratory patterns and positioning of all immune cells. Although chemokines were initially appreciated as important mediators of acute inflammation, we now know that this complex system of approximately 50 endogenous chemokine ligands and 20 G protein-coupled seven-transmembrane signaling receptors is also critical for the generation of primary and secondary adaptive cellular and humoral immune responses. Recent studies demonstrate important roles for the chemokine system in the priming of naive T cells, in cell fate decisions such as effector and memory cell differentiation, and in regulatory T cell function. In this review, we focus on recent advances in understanding how the chemokine system orchestrates immune cell migration and positioning at the organismic level in homeostasis, in acute inflammation, and during the generation and regulation of adoptive primary and secondary immune responses in the lymphoid system and peripheral nonlymphoid tissue.
Assuntos
Quimiocinas/metabolismo , Imunidade/fisiologia , Receptores de Quimiocinas/metabolismo , Imunidade Adaptativa/fisiologia , Animais , Movimento Celular/imunologia , Homeostase , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunidade Inata/fisiologia , Memória Imunológica , Inflamação/imunologia , Inflamação/metabolismo , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery.
Assuntos
Microbioma Gastrointestinal , Infecções por HIV/imunologia , Infecções por HIV/microbiologia , Terapia Antirretroviral de Alta Atividade , Biodiversidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Quimiocinas/sangue , Estudos de Coortes , Glicólise , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Humanos , Inflamação/genética , Inflamação/patologia , Mitocôndrias/metabolismo , Monócitos/metabolismo , Ácidos Nucleicos/sangue , Análise de Componente Principal , Serratia/fisiologia , Células Th1/imunologia , Células Th2/imunologia , Transcrição Gênica , Uganda , Carga Viral/imunologiaRESUMO
Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.
Assuntos
Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Proteínas Morfogenéticas Ósseas/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Compartimento Celular , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Estudos de Coortes , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA/genética , Células Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade , Inflamação/patologia , Monócitos/patologia , Células Mieloides/patologia , Neutrófilos/patologia , Células Estromais/metabolismo , Linfócitos T/metabolismo , Transcrição GênicaRESUMO
Despite remarkable clinical efficacy of immune checkpoint blockade (ICB) in cancer treatment, ICB benefits for triple-negative breast cancer (TNBC) remain limited. Through pooled in vivo CRISPR knockout (KO) screens in syngeneic TNBC mouse models, we found that deletion of the E3 ubiquitin ligase Cop1 in cancer cells decreases secretion of macrophage-associated chemokines, reduces tumor macrophage infiltration, enhances anti-tumor immunity, and strengthens ICB response. Transcriptomics, epigenomics, and proteomics analyses revealed that Cop1 functions through proteasomal degradation of the C/ebpδ protein. The Cop1 substrate Trib2 functions as a scaffold linking Cop1 and C/ebpδ, which leads to polyubiquitination of C/ebpδ. In addition, deletion of the E3 ubiquitin ligase Cop1 in cancer cells stabilizes C/ebpδ to suppress expression of macrophage chemoattractant genes. Our integrated approach implicates Cop1 as a target for improving cancer immunotherapy efficacy in TNBC by regulating chemokine secretion and macrophage infiltration in the tumor microenvironment.
Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Imunoterapia , Macrófagos/enzimologia , Neoplasias/imunologia , Neoplasias/terapia , Proteínas Nucleares/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Proteína 9 Associada à CRISPR/metabolismo , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Quimiotaxia , Modelos Animais de Doenças , Biblioteca Gênica , Humanos , Evasão da Resposta Imune , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteólise , Especificidade por Substrato , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/terapiaRESUMO
Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes.
Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Substâncias Protetoras/farmacologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Ligação Competitiva , COVID-19/imunologia , COVID-19/virologia , Quimiocinas/metabolismo , Chlorocebus aethiops , Células HEK293 , Humanos , Fragmentos Fab das Imunoglobulinas/metabolismo , Imunoglobulina G/metabolismo , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Modelos Moleculares , Mutagênese/genética , Testes de Neutralização , Domínios Proteicos , Células VeroRESUMO
Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.
Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Autoanticorpos , Síndrome de COVID-19 Pós-Aguda , QuimiocinasRESUMO
Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Vírus de RNA/imunologia , Animais , COVID-19 , Células Cultivadas , Quimiocinas/genética , Quimiocinas/imunologia , Infecções por Coronavirus/genética , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Inflamação/virologia , Interferons/genética , Interferons/imunologia , Pandemias , Pneumonia Viral/genética , Vírus de RNA/classificação , SARS-CoV-2 , Transcrição GênicaRESUMO
The SARS-CoV-2 pandemic has caused extreme human suffering and economic harm. We generated and characterized a new mouse-adapted SARS-CoV-2 virus that captures multiple aspects of severe COVID-19 disease in standard laboratory mice. This SARS-CoV-2 model exhibits the spectrum of morbidity and mortality of COVID-19 disease as well as aspects of host genetics, age, cellular tropisms, elevated Th1 cytokines, and loss of surfactant expression and pulmonary function linked to pathological features of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). This model can rapidly access existing mouse resources to elucidate the role of host genetics, underlying molecular mechanisms governing SARS-CoV-2 pathogenesis, and the protective or pathogenic immune responses related to disease severity. The model promises to provide a robust platform for studies of ALI and ARDS to evaluate vaccine and antiviral drug performance, including in the most vulnerable populations (i.e., the aged) using standard laboratory mice.
Assuntos
Lesão Pulmonar Aguda/patologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Animais , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , COVID-19 , Linhagem Celular , Quimiocinas/sangue , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Citocinas/sangue , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/patologia , Pulmão/fisiologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório/patologia , SARS-CoV-2 , Índice de Gravidade de Doença , Taxa de SobrevidaRESUMO
Acute psychological stress has long been known to decrease host fitness to inflammation in a wide variety of diseases, but how this occurs is incompletely understood. Using mouse models, we show that interleukin-6 (IL-6) is the dominant cytokine inducible upon acute stress alone. Stress-inducible IL-6 is produced from brown adipocytes in a beta-3-adrenergic-receptor-dependent fashion. During stress, endocrine IL-6 is the required instructive signal for mediating hyperglycemia through hepatic gluconeogenesis, which is necessary for anticipating and fueling "fight or flight" responses. This adaptation comes at the cost of enhancing mortality to a subsequent inflammatory challenge. These findings provide a mechanistic understanding of the ontogeny and adaptive purpose of IL-6 as a bona fide stress hormone coordinating systemic immunometabolic reprogramming. This brain-brown fat-liver axis might provide new insights into brown adipose tissue as a stress-responsive endocrine organ and mechanistic insight into targeting this axis in the treatment of inflammatory and neuropsychiatric diseases.
Assuntos
Tecido Adiposo Marrom/metabolismo , Interleucina-6/metabolismo , Estresse Psicológico , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Transplante de Medula Óssea , Encéfalo/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Gluconeogênese , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Interleucina-6/sangue , Interleucina-6/genética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Adrenérgicos beta 3/metabolismo , Receptores de Interleucina-6/metabolismo , Proteína Desacopladora 1/deficiência , Proteína Desacopladora 1/genéticaRESUMO
Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. We observed a striking accumulation of CD8 T cells with highly cytotoxic and proliferative states and no evidence of regulatory T cell depletion. T cell receptor (TCR) sequence analysis demonstrated that a substantial fraction of colitis-associated CD8 T cells originated from tissue-resident populations, explaining the frequently early onset of colitis symptoms following treatment initiation. Our analysis also identified cytokines, chemokines, and surface receptors that could serve as therapeutic targets for colitis and potentially other inflammatory side effects of checkpoint blockade.
Assuntos
Linfócitos T CD8-Positivos/citologia , Antígeno CTLA-4/imunologia , Colite/metabolismo , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/efeitos adversos , Células Mieloides/metabolismo , Receptores de Quimiocinas/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Antígeno CTLA-4/metabolismo , Quimiocinas/metabolismo , Colite/tratamento farmacológico , Colite/genética , Colite/imunologia , Citocinas/metabolismo , Citometria de Fluxo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Melanoma/genética , Melanoma/imunologia , Melanoma/metabolismo , Família Multigênica , Células Mieloides/citologia , RNA-Seq , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores CXCR3/genética , Receptores CXCR3/metabolismo , Receptores CXCR6/genética , Receptores CXCR6/metabolismo , Receptores de Quimiocinas/genética , Análise de Célula Única , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismoRESUMO
Tumor-associated macrophages are composed of distinct populations arising from monocytes or tissue macrophages, with a poorly understood link to disease pathogenesis. Here, we demonstrate that mouse monocyte migration was supported by glutaminyl-peptide cyclotransferase-like (QPCTL), an intracellular enzyme that mediates N-terminal modification of several substrates, including the monocyte chemoattractants CCL2 and CCL7, protecting them from proteolytic inactivation. Knockout of Qpctl disrupted monocyte homeostasis, attenuated tumor growth and reshaped myeloid cell infiltration, with loss of monocyte-derived populations with immunosuppressive and pro-angiogenic profiles. Antibody targeting of the receptor CSF1R, which more broadly eliminates tumor-associated macrophages, reversed tumor growth inhibition in Qpctl-/- mice and prevented lymphocyte infiltration. Modulation of QPCTL synergized with anti-PD-L1 to expand CD8+ T cells and limit tumor growth. QPCTL inhibition constitutes an effective approach for myeloid cell-targeted cancer immunotherapy.
Assuntos
Aminoaciltransferases , Linfócitos T CD8-Positivos , Quimiocinas , Neoplasias , Aminoaciltransferases/genética , Aminoaciltransferases/metabolismo , Animais , Linfócitos T CD8-Positivos/patologia , Quimiocinas/metabolismo , Imunoterapia , Infiltração Leucêmica , Camundongos , Camundongos Knockout , Monócitos , Neoplasias/imunologiaRESUMO
Only a handful of the more than 100,000 fungal species on our planet cause disease in humans, yet the number of life-threatening fungal infections in patients has recently skyrocketed as a result of advances in medical care that often suppress immunity intensely. This emerging crisis has created pressing needs to clarify immune defense mechanisms against fungi, with the ultimate goal of therapeutic applications. Herein, we describe recent insights in understanding the mammalian immune defenses deployed against pathogenic fungi. The review focuses on adaptive immune responses to the major medically important fungi and emphasizes how dendritic cells and subsets in various anatomic compartments respond to fungi, recognize their molecular patterns, and signal responses that nurture and shape the differentiation of T cell subsets and B cells. Also emphasized is how the latter deploy effector and regulatory mechanisms that eliminate these nasty invaders while also constraining collateral damage to vital tissue.
Assuntos
Imunidade Adaptativa , Fungos/imunologia , Micoses/imunologia , Animais , Diferenciação Celular/imunologia , Quimiocinas/imunologia , Citocinas/imunologia , Células Dendríticas/imunologia , Humanos , Imunidade Inata , Imunoglobulinas/imunologia , Receptores de Reconhecimento de Padrão/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Reduced infiltration of anti-tumor lymphocytes remains a major cause of tumor immune evasion and is correlated with poor cancer survival. Here, we found that upregulation of regulator of G protein signaling (RGS)1 in helper TH1 cells and cytotoxic T lymphocytes (CTLs) reduced their trafficking to and survival in tumors and was associated with shorter survival of patients with breast and lung cancer. RGS1 was upregulated by type II interferon (IFN)-signal transducer and activator of transcription (STAT)1 signaling and impaired trafficking of circulating T cells to tumors by inhibiting calcium influx and suppressing activation of the kinases ERK and AKT. RGS1 knockdown in adoptively transferred tumor-specific CTLs significantly increased their infiltration and survival in breast and lung tumor grafts and effectively inhibited tumor growth in vivo, which was further improved when combined with programmed death ligand (PD-L)1 checkpoint inhibition. Our findings reveal RGS1 is important for tumor immune evasion and suggest that targeting RGS1 may provide a new strategy for tumor immunotherapy.
Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Quimiotaxia de Leucócito , Linfócitos do Interstício Tumoral/metabolismo , Proteínas RGS/metabolismo , Subpopulações de Linfócitos T/metabolismo , Animais , Apoptose , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/terapia , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Técnicas de Cocultura , Citotoxicidade Imunológica , Feminino , Humanos , Imunoterapia Adotiva , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/transplante , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Microscopia de Vídeo , Proteínas RGS/genética , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/transplante , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Fatores de Tempo , Imagem com Lapso de Tempo , Células Tumorais Cultivadas , Evasão TumoralRESUMO
Diet profoundly influences physiology. Whereas over-nutrition elevates risk for disease via its influence on immunity and metabolism, caloric restriction and fasting appear to be salutogenic. Despite multiple correlations observed between diet and health, the underlying biology remains unclear. Here, we identified a fasting-induced switch in leukocyte migration that prolongs monocyte lifespan and alters susceptibility to disease in mice. We show that fasting during the active phase induced the rapid return of monocytes from the blood to the bone marrow. Monocyte re-entry was orchestrated by hypothalamic-pituitary-adrenal (HPA) axis-dependent release of corticosterone, which augmented the CXCR4 chemokine receptor. Although the marrow is a safe haven for monocytes during nutrient scarcity, re-feeding prompted mobilization culminating in monocytosis of chronologically older and transcriptionally distinct monocytes. These shifts altered response to infection. Our study shows that diet-in particular, a diet's temporal dynamic balance-modulates monocyte lifespan with consequences for adaptation to external stressors.