RESUMO
Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours1-4, but the cause of this link is unknown. Here we show that tumour cells disrupt methionine metabolism in CD8+ T cells, thereby lowering intracellular levels of methionine and the methyl donor S-adenosylmethionine (SAM) and resulting in loss of dimethylation at lysine 79 of histone H3 (H3K79me2). Loss of H3K79me2 led to low expression of STAT5 and impaired T cell immunity. Mechanistically, tumour cells avidly consumed methionine and outcompeted T cells for methionine by expressing high levels of the methionine transporter SLC43A2. Genetic and biochemical inhibition of tumour SLC43A2 restored H3K79me2 in T cells, thereby boosting spontaneous and checkpoint-induced tumour immunity. Moreover, methionine supplementation improved the expression of H3K79me2 and STAT5 in T cells, and this was accompanied by increased T cell immunity in tumour-bearing mice and patients with colon cancer. Clinically, tumour SLC43A2 correlated negatively with T cell histone methylation and functional gene signatures. Our results identify a mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumour microenvironment. Thus, cancer methionine consumption is an immune evasion mechanism, and targeting cancer methionine signalling may provide an immunotherapeutic approach.
Assuntos
Sistema L de Transporte de Aminoácidos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Histonas/metabolismo , Metionina/metabolismo , Metilação , Neoplasias/metabolismo , Sistema L de Transporte de Aminoácidos/deficiência , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Epigênese Genética , Feminino , Histonas/química , Humanos , Camundongos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Receptores de Antígenos de Linfócitos T/metabolismo , Fator de Transcrição STAT5/metabolismoRESUMO
Cancer immunotherapy restores or enhances the effector function of CD8+ T cells in the tumour microenvironment1,2. CD8+ T cells activated by cancer immunotherapy clear tumours mainly by inducing cell death through perforin-granzyme and Fas-Fas ligand pathways3,4. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent accumulation of lipid peroxide5,6. Although it has been investigated in vitro7,8, there is emerging evidence that ferroptosis might be implicated in a variety of pathological scenarios9,10. It is unclear whether, and how, ferroptosis is involved in T cell immunity and cancer immunotherapy. Here we show that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased ferroptosis contributes to the anti-tumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFNγ) released from CD8+ T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system xc-, impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced ferroptosis in tumour cells. Expression of system xc- was negatively associated, in cancer patients, with CD8+ T cell signature, IFNγ expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNγ and CD8. Thus, T cell-promoted tumour ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Ferroptose , Imunoterapia , Neoplasias/imunologia , Neoplasias/terapia , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Antígeno B7-H1/antagonistas & inibidores , Linhagem Celular Tumoral , Cisteína/metabolismo , Feminino , Ferroptose/efeitos dos fármacos , Cadeia Pesada da Proteína-1 Reguladora de Fusão/metabolismo , Humanos , Interferon gama/imunologia , Peroxidação de Lipídeos , Melanoma/genética , Melanoma/imunologia , Melanoma/metabolismo , Melanoma/terapia , Camundongos , Neoplasias/metabolismo , Nivolumabe/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: Haloxylon ammodendron holds significance as an ecological plant, showcasing remarkable adaptability to desert conditions, halophytic environments, and sand fixation. With its potential for carbon sequestration, it emerges as a promising candidate for environmental sustainability. Furthermore, it serves as a valuable C4 plant model, offering insights into the genetic foundations of extreme drought tolerance. Despite the availability of plastid and nuclear genomes, the absence of a mitochondrial genome (mitogenome or mtDNA) hinders a comprehensive understanding of its its mtDNA structure, organization, and phylogenetic implications. RESULTS: In the present study, the mitochondrial genome of H. ammodendron was assembled and annotated, resulting in a multi-chromosomal configuration with two circular chromosomes. The mtDNA measured 210,149 bp in length and contained 31 protein-coding genes, 18 tRNA and three rRNA. Our analysis identified a total of 66 simple sequence repeats along with 27 tandem repeats, 312 forward repeats, and 303 palindromic repeats were found. Notably, 17 sequence fragments displayed homology between the mtDNA and chloroplast genome (cpDNA), spanning 5233 bp, accounting for 2.49% of the total mitogenome size. Additionally, we predicted 337 RNA editing sites, all of the C-to-U conversion type. Phylogenetic inference confidently placed H. ammodendron in the Amaranthacea family and its close relative, Suaeda glacum. CONCLUSIONS: H. ammodendron mtDNA showed a multi-chromosomal structure with two fully circularized molecules. This newly characterized mtDNA represents a valuable resource for gaining insights into the basis of mtDNA structure variation within Caryophyllales and the evolution of land plants, contributing to their identification, and classification.
Assuntos
Chenopodiaceae , Genoma Mitocondrial , Plantas Tolerantes a Sal/genética , Filogenia , Chenopodiaceae/genética , DNA Mitocondrial/genéticaRESUMO
Human/simian immunodeficiency virus (HIV/SIV) infection can cause severe depletion of CD4(+) T cells in both plasma and mucosa; it also results in damage to the gut mucosa barrier, which makes the condition more conducive to microbial translocation. In this study, we used SIV-infected Chinese rhesus macaques to quantify the extent of microbial translocation and the function of immune cells in the entire gastrointestinal tract and to compare their differences between rapid and slow progressors. The results showed that in the slow progressors, microbial products translocated considerably and deeply into the lamina propria of the gut; the tissue macrophages had no significant differences compared with the rapid progressors, but there was a slightly higher percentage of mucosal CD8(+) T cells and a large amount of extracellular microbial products in the lamina propria of the intestinal mucosa of the slow progressors. The data suggested that although microbial translocation increased markedly, the mucosal macrophages and CD8(+) T cells were insufficient to clear the infiltrated microbes in the slow progressors. Also, therapies aimed at suppressing the translocation of microbial products in the mucosa could help to delay the progression of SIV disease.
Assuntos
Microbioma Gastrointestinal , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Progressão da Doença , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Mucosa Intestinal/virologia , Contagem de Linfócitos , Macaca mulatta , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Fagocitose/imunologia , Carga ViralRESUMO
The tree shrew is becoming an attractive experimental animal model for human breast cancer owing to a closer relationship to primates/humans than rodents. Tree shrews are superior to classical primates because tree shrew are easier to manipulate, maintain and propagate. It is required to establish a high-efficiency tree shrew breast cancer model for etiological research and drug assessment. Our previous studies suggest that 7,12-dimethylbenz(a)anthracene (DMBA) and medroxyprogesterone acetate (MPA) induce breast tumors in tree shrews with a low frequency (<50%) and long latency (â¼ 7-month), making these methods less than ideal. We induced mammary tumors in tree shrew (Tupaia belangeri chinensis) by injection of lentivirus expressing the PyMT oncogene into mammary ducts of 22 animals. Most tree shrews developed mammary tumors with a latency of about three weeks, and by 7 weeks all injected tree shrews had developed mammary tumors. Among these, papillary carcinoma is the predominant tumor type. One case showed lymph node and lung metastasis. Interestingly, the expression levels of phosphorylated AKT, ERK and STAT3 were elevated in 41-68% of PyMT-induced mammary tumors, but not all tumors. Finally, we observed that the growth of PyMT-induced tree shrew mammary tumors was significantly inhibited by Cisplatin and Epidoxorubicin. PyMT-induced tree shrew mammary tumor model may be suitable for further breast cancer research and drug development, due to its high efficiency and short latency.
Assuntos
Antígenos Virais de Tumores/genética , Modelos Animais de Doenças , Neoplasias Mamárias Animais/etiologia , Polyomavirus/imunologia , Tupaiidae , Animais , Carcinoma Papilar/etiologia , Células Epiteliais/patologia , Receptor alfa de Estrogênio/análise , Feminino , Lentivirus/genética , Neoplasias Mamárias Animais/química , Neoplasias Mamárias Animais/tratamento farmacológico , Fator de Transcrição STAT3/metabolismoRESUMO
The KLF5 (Krüppel-like factor 5) transcription factor is specifically expressed in a subset of estrogen receptor α-negative breast cancers. Although KLF5 promotes breast cancer cell cycle progression, survival, and tumorigenesis, the mechanism by which KLF5 promotes breast cancer is still not entirely understood. Here, we demonstrate that mPGES1, encoding microsomal prostaglandin E2 synthase 1 (mPGES1), is a KLF5 direct downstream target gene. KLF5 overexpression or knockdown positively altered the levels of mPGES1 mRNA and protein in multiple breast cell lines. 12-O-Tetradecanoylphorbol-13-acetate induced the expression of both KLF5 and mPGES1 in dosage- and time-dependent manners. The induction of KLF5 was essential for 12-O-tetradecanoylphorbol-13-acetate to induce mPGES1 expression. Additionally, KLF5 bound to the mPGES1 gene proximal promoter and activated its transcription. Both KLF5 and mPGES1 promoted prostaglandin E2 production; regulated p21, p27, and Survivin downstream gene expression; and likewise stimulated cell proliferation. Overexpression of mPGES1 partially rescued the KLF5 knockdown-induced downstream gene expression changes and growth arrest in MCF10A cells. Finally, we demonstrate that the expression of mPGES1 was positively correlated with the estrogen receptor α/progesterone receptor/HER2 triple-negative status. These findings suggest that mPGES1 is a target gene of KLF5, making it a new biomarker and a potential therapeutic target for triple-negative breast cancers.
Assuntos
Neoplasias da Mama/metabolismo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Oxirredutases Intramoleculares/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Transcrição Gênica , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Imunoprecipitação da Cromatina , Feminino , Humanos , Imuno-Histoquímica , Proteínas Inibidoras de Apoptose/metabolismo , Células MCF-7 , Microssomos/metabolismo , Ésteres de Forbol/metabolismo , Prostaglandina-E Sintases , SurvivinaRESUMO
The MHC class I (MHC I) molecules play a pivotal role in the regulation of immune responses by presenting antigenic peptides to CTLs and by regulating cytolytic activities of NK cells. In this article, we show that MHC I A in rhesus macaques can be alternatively spliced, generating a novel MHC I A isoform (termed "MHC I A-sv1") devoid of α(3) domain. Despite the absence of ß2-microglobulin (ß2m), the MHC I A-sv1 proteins reached the cell surface of K562-transfected cells as endoglycosidase H-sensitive glycoproteins that could form disulfide-bonded homodimers. Cycloheximide-based protein chase experiments showed that the MHC I A-sv1 proteins were more stable than the full-length MHC I A in transiently or stably transfected cell lines. Of particular interest, our studies demonstrated that MHC I A-sv1 could form ß2m-free heterodimers with its full-length protein in mammalian cells. The formation of heterodimers was accompanied by a reduction in full-length MHC I A ubiquitination and consequent stabilization of the protein. Taken together, these results demonstrated that MHC I A-sv1 and MHC I A can form a novel heterodimeric complex as a result of the displacement of ß2m and illustrated the relevance of regulated MHC I A protein degradation in the ß2m-free heterodimerization-dependent control, which may have some implications for the MHC I A splice variant in the fine tuning of classical MHC I A/TCR and MHC I A/killer cell Ig-like receptor interactions.
Assuntos
Processamento Alternativo/imunologia , Regulação para Baixo/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Isoformas de Proteínas/metabolismo , Ubiquitina/antagonistas & inibidores , Ubiquitina/fisiologia , Microglobulina beta-2/deficiência , Microglobulina beta-2/metabolismo , Processamento Alternativo/genética , Animais , Dissulfetos/metabolismo , Regulação para Baixo/genética , Glicoproteínas/genética , Glicoproteínas/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Células K562 , Macaca mulatta , Camundongos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Isoformas de Proteínas/genética , Multimerização Proteica , Processamento de Proteína Pós-Traducional/genética , Processamento de Proteína Pós-Traducional/imunologia , Deleção de Sequência/genética , Deleção de Sequência/imunologia , Transfecção , Ubiquitina/metabolismo , Microglobulina beta-2/genéticaRESUMO
Tumor necrosis factor-α-induced protein 8-like 3 (TNFAIP8L3 or TIPE3) functions as a transfer protein for lipid second messengers. TIPE3 is highly upregulated in several human cancers and has been established to significantly promote tumor cell proliferation, migration, and invasion and inhibit the apoptosis of cancer cells. Thus, inhibiting the function of TIPE3 is expected to be an effective strategy against cancer. The advancement of artificial intelligence (AI)-driven drug development has recently invigorated research in anti-cancer drug development. In this work, we incorporated DFCNN, Autodock Vina docking, DeepBindBC, MD, and metadynamics to efficiently identify inhibitors of TIPE3 from a ZINC compound dataset. Six potential candidates were selected for further experimental study to validate their anti-tumor activity. Among these, three small-molecule compounds (K784-8160, E745-0011, and 7238-1516) showed significant anti-tumor activity in vitro, leading to reduced tumor cell viability, proliferation, and migration and enhanced apoptotic tumor cell death. Notably, E745-0011 and 7238-1516 exhibited selective cytotoxicity toward tumor cells with high TIPE3 expression while having little or no effect on normal human cells or tumor cells with low TIPE3 expression. A molecular docking analysis further supported their interactions with TIPE3, highlighting hydrophobic interactions and their shared interaction residues and offering insights for designing more effective inhibitors. Taken together, this work demonstrates the feasibility of incorporating deep learning and MD simulations in virtual drug screening and provides inhibitors with significant potential for anti-cancer drug development against TIPE3-.
Assuntos
Antineoplásicos , Proliferação de Células , Peptídeos e Proteínas de Sinalização Intracelular , Humanos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Aprendizado Profundo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Tumor-associated macrophages (TAMs) shape tumor immunity and therapeutic efficacy. However, it is poorly understood whether and how post-translational modifications (PTMs) intrinsically affect the phenotype and function of TAMs. Here, we reveal that peptidylarginine deiminase 4 (PAD4) exhibits the highest expression among common PTM enzymes in TAMs and negatively correlates with the clinical response to immune checkpoint blockade. Genetic and pharmacological inhibition of PAD4 in macrophages prevents tumor progression in tumor-bearing mouse models, accompanied by an increase in macrophage major histocompatibility complex (MHC) class II expression and T cell effector function. Mechanistically, PAD4 citrullinates STAT1 at arginine 121, thereby promoting the interaction between STAT1 and protein inhibitor of activated STAT1 (PIAS1), and the loss of PAD4 abolishes this interaction, ablating the inhibitory role of PIAS1 in the expression of MHC class II machinery in macrophages and enhancing T cell activation. Thus, the PAD4-STAT1-PIAS1 axis is an immune restriction mechanism in macrophages and may serve as a cancer immunotherapy target.
Assuntos
Hidrolases , Processamento de Proteína Pós-Traducional , Camundongos , Animais , Desiminases de Arginina em Proteínas/metabolismo , Proteína-Arginina Desiminase do Tipo 4/genética , Proteína-Arginina Desiminase do Tipo 4/metabolismo , Hidrolases/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Macrófagos/metabolismoRESUMO
Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that PIKFYVE is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy. Genetic and pharmacological studies demonstrate that PIKfyve ablation enhances the function of CD11c+ cells (predominantly dendritic cells) via selectively altering the non-canonical NF-κB pathway. Both loss of Pikfyve in CD11c+ cells and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively regulates the function of CD11c+ cells, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.
Assuntos
Antígeno CD11c , Células Dendríticas , Morfolinas , Fosfatidilinositol 3-Quinases , Animais , Feminino , Humanos , Camundongos , Antígeno CD11c/metabolismo , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/efeitos dos fármacos , Hidrazonas , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Neoplasias/imunologia , Neoplasias/genética , Neoplasias/terapia , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas , Linfócitos T/imunologia , MasculinoRESUMO
The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-κB pathway. Both loss of Pikfyve in DCs and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.
RESUMO
Monocytes are highly plastic innate immune cells that display significant heterogeneity during homeostasis, inflammation, and tumorigenesis. Tumor-induced systemic and local microenvironmental changes influence the phenotype, differentiation, and distribution of monocytes. Meanwhile, monocytes and their related cell subsets perform an important regulatory role in the development of many cancers by affecting tumor growth or metastasis. Thanks to recent advances in single-cell technologies, the nature of monocyte heterogeneity and subset-specific functions have become increasingly clear, making it possible to systematically analyze subset-specific roles of monocytes in tumorigenesis. In this review, we discuss recent discoveries related to monocytes and tumorigenesis, and new strategies for tumor biomarker identification and anti-tumor immunotherapy.
Assuntos
Monócitos , Neoplasias , Humanos , Monócitos/patologia , Carcinogênese/patologia , Neoplasias/patologia , Transformação Celular Neoplásica/patologia , Imunoterapia , Biomarcadores TumoraisRESUMO
CD4(+)CD25(high) regulatory T cells (Treg), which are a specialized subset of T cells, play an important role in the prevention of autoimmune diseases, maintenance of immune system homeostasis and tolerance to self-antigens. Chinese rhesus macaques (CRMs) are widely used in preclinical research on potential therapeutic drugs, vaccines and mechanisms of human diseases. However, the basic immunological characterization of Treg cells of CRMs has not been well established. To characterize Treg cells, peripheral blood of 43 adult CRMs was analyzed for CD4+ T lymphocytes by flow cytometry. It was found that Treg cells ranged from 1.52% to 11.1% of CD4+ T cells, and the average value was 5.7%. With our SIV-infected CRM model, through further studies, it was found that Treg cells in peripheral blood increased both in relative and absolute quantities. Moreover, Treg cells maintained their functions by suppressing Th1 cytokine secretion of their target cells. The results show that Treg cells might render cellular immunity against SIV viruses dysfunctional during the early stage after infection.
Assuntos
Infecções por HIV/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Linfócitos T Reguladores/imunologia , Animais , Células Cultivadas , China , Modelos Animais de Doenças , Feminino , Infecções por HIV/virologia , HIV-1/imunologia , HIV-1/fisiologia , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Macaca fascicularis , Macaca mulatta , Masculino , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Linfócitos T Reguladores/virologiaRESUMO
Macrophages residing in various tissues play crucial roles in innate immunity, tissue repair, and immune homeostasis. The development and differentiation of macrophages in non-lymphoid tissues are highly regulated by the tissue microenvironment. Peritoneum provides a unique metastatic niche for certain types of tumor cells. As the dominant immune cell type in peritoneal cavity, macrophages control the immune response to tumor and influence the efficacy of anti-tumor therapy. Considering the heterogeneity of macrophages in origin, metabolism, and function, it is always challenging to define the precise roles of macrophages in tumor microenvironment. We review here recent progresses in peritoneal resident macrophage research in the context of physiological and metastatic tumor conditions, which may benefit the development of new anti-tumor therapies through targeting macrophages.
RESUMO
Metastasis is the leading cause of cancer-related death. The interactions between circulating tumor cells and endothelial adhesion molecules in distant organs is a key step during extravasation in hematogenous metastasis. Surgery is a common intervention for most primary solid tumors. However, surgical trauma-related systemic inflammation facilitates distant tumor metastasis by increasing the spread and adhesion of tumor cells to vascular endothelial cells (ECs). Currently, there are no effective interventions to prevent distant metastasis. Here, we show that HECTD3 deficiency in ECs significantly reduces tumor metastasis in multiple mouse models. HECTD3 depletion downregulates expression of adhesion molecules, such as VCAM-1, ICAM-1 and E-selectin, in mouse primary ECs and HUVECs stimulated by inflammatory factors and inhibits adhesion of tumor cells to ECs both in vitro and in vivo. We demonstrate that HECTD3 promotes stabilization, nuclear localization and kinase activity of IKKα by ubiquitinating IKKα with K27- and K63-linked polyubiquitin chains at K296, increasing phosphorylation of histone H3 to promote NF-κB target gene transcription. Knockout of HECTD3 in endothelium significantly inhibits tumor cells lung colonization, while conditional knockin promotes that. IKKα kinase inhibitors prevented LPS-induced pulmonary metastasis. These findings reveal the promotional role of the HECTD3-IKKα axis in tumor hematogenous metastasis and provide a potential strategy for tumor metastasis prevention.
Assuntos
Células Endoteliais , Neoplasias , Animais , Células Endoteliais/metabolismo , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Inflamação/genética , Inflamação/metabolismo , Camundongos , Camundongos Knockout , Neoplasias/genética , Neoplasias/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Autophagy is a regulated mechanism that removes unnecessary or dysfunctional cellular components and recycles metabolic substrates. In response to stress signals in the tumour microenvironment, the autophagy pathway is altered in tumour cells and immune cells - thereby differentially affecting tumour progression, immunity and therapy. In this Review, we summarize our current understanding of the immunologically associated roles and modes of action of the autophagy pathway in cancer progression and therapy, and discuss potential approaches targeting autophagy to enhance antitumour immunity and improve the efficacy of current cancer therapy.
Assuntos
Antineoplásicos/uso terapêutico , Autofagia , Imunoterapia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Microambiente Tumoral/imunologia , Animais , Humanos , Neoplasias/patologiaRESUMO
Immunotherapy induces durable clinical responses in a fraction of patients with cancer. However, therapeutic resistance poses a major challenge to current immunotherapies. Here, we identify that expression of tumor stanniocalcin 1 (STC1) correlates with immunotherapy efficacy and is negatively associated with patient survival across diverse cancer types. Gain- and loss-of-function experiments demonstrate that tumor STC1 supports tumor progression and enables tumor resistance to checkpoint blockade in murine tumor models. Mechanistically, tumor STC1 interacts with calreticulin (CRT), an "eat-me" signal, and minimizes CRT membrane exposure, thereby abrogating membrane CRT-directed phagocytosis by antigen-presenting cells (APCs), including macrophages and dendritic cells. Consequently, this impairs APC capacity of antigen presentation and T cell activation. Thus, tumor STC1 inhibits APC phagocytosis and contributes to tumor immune evasion and immunotherapy resistance. We suggest that STC1 is a previously unappreciated phagocytosis checkpoint and targeting STC1 and its interaction with CRT may sensitize to cancer immunotherapy.
Assuntos
Glicoproteínas/metabolismo , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Fagocitose/imunologia , Evasão Tumoral/imunologia , Animais , Apresentação de Antígeno/imunologia , Imunoterapia/métodos , Macrófagos/metabolismo , Camundongos , Fagocitose/efeitos dos fármacos , Receptores Imunológicos/imunologiaRESUMO
BACKGROUND: Several studies have demonstrated that SIV infection progresses more slowly to experimental AIDS in Chinese rhesus macaques (Ch Rhs) than in Indian rhesus macaques (Ind Rhs). Here we investigated the dynamic and functional changes in dendritic cell (DC) subsets in SIVmac239-infected Ch Rhs. RESULTS: The numbers of both mDC and pDC strongly fluctuated but were not significantly changed during the acute and chronic phases of infection. However, the concentration of both poly (I:C)-induced IL-12 and HSV-1-induced IFN-α significantly increased in the acute phase of infection but returned to normal levels at the chronic phase of infection. The peak of IFN-α emerged earlier than that of IL-12, and it had a significantly positive correlation with IL-12, which indicated that IFN-α may initiate the immune activation. We also found that only the concentration of IFN-α was positively correlated with CD4+ T-cell counts, but it was negatively correlated with viral load. CONCLUSION: High levels of IFN-α in the early stage of infection may contribute to effective control of virus replication, and normal levels of IFN-α during chronic infection may help Ch Rhs resist the disease progression. The change in DC subsets dynamics and cytokine production may help further our understanding of why Ch Rhs are able to live longer without progressing to an AIDS-like illness.
Assuntos
Células Dendríticas/imunologia , Interferon-alfa/biossíntese , Interleucina-12/biossíntese , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia , Animais , Contagem de Linfócito CD4 , Contagem de Células , Células Cultivadas , Leucócitos Mononucleares/imunologia , Macaca mulatta , MasculinoRESUMO
Tumor-associated macrophages (TAMs) affect cancer progression and therapy. Ovarian carcinoma often metastasizes to the peritoneal cavity. Here, we found 2 peritoneal macrophage subsets in mice bearing ID8 ovarian cancer based on T cell immunoglobulin and mucin domain containing 4 (Tim-4) expression. Tim-4+ TAMs were embryonically originated and locally sustained while Tim-4- TAMs were replenished from circulating monocytes. Tim-4+ TAMs, but not Tim-4- TAMs, promoted tumor growth in vivo. Relative to Tim-4- TAMs, Tim-4+ TAMs manifested high oxidative phosphorylation and adapted mitophagy to alleviate oxidative stress. High levels of arginase-1 in Tim-4+ TAMs contributed to potent mitophagy activities via weakened mTORC1 activation due to low arginine resultant from arginase-1-mediated metabolism. Furthermore, genetic deficiency of autophagy element FAK family-interacting protein of 200 kDa resulted in Tim-4+ TAM loss via ROS-mediated apoptosis and elevated T cell immunity and ID8 tumor inhibition in vivo. Moreover, human ovarian cancer-associated macrophages positive for complement receptor of the immunoglobulin superfamily (CRIg) were transcriptionally, metabolically, and functionally similar to murine Tim-4+ TAMs. Thus, targeting CRIg+ (Tim-4+) TAMs may potentially treat patients with ovarian cancer with peritoneal metastasis.
Assuntos
Autofagia , Macrófagos Peritoneais/patologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/fisiologia , Neoplasias Ovarianas/patologia , Estresse Oxidativo , Neoplasias Peritoneais/secundário , Adaptação Fisiológica , Animais , Proteínas Relacionadas à Autofagia/fisiologia , Feminino , Humanos , Antígenos Comuns de Leucócito/fisiologia , Macrófagos Peritoneais/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/metabolismo , Receptores CCR2/fisiologiaRESUMO
Lysine-63-linked (K63-linked) polyubiquitination of TRAF3 coordinates the engagement of pattern-recognition receptors with recruited adaptor proteins and downstream activator TBK1 in pathways that induce type I IFN. Whether autoubiquitination or other E3 ligases mediate K63-linked TRAF3 polyubiquitination remains unclear. We demonstrated that mice deficient in the E3 ligase gene Hectd3 remarkably increased host defense against infection by intracellular bacteria Francisella novicida, Mycobacterium, and Listeria by limiting bacterial dissemination. In the absence of HECTD3, type I IFN response was impaired during bacterial infection both in vivo and in vitro. HECTD3 regulated type I IFN production by mediating K63-linked polyubiquitination of TRAF3 at residue K138. The catalytic domain of HECTD3 regulated TRAF3 K63 polyubiquitination, which enabled TRAF3-TBK1 complex formation. Our study offers insights into mechanisms of TRAF3 modulation and provides potential therapeutic targets against infections by intracellular bacteria and inflammatory diseases.