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1.
Pharmacol Res ; 174: 105966, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34728366

RESUMO

Microbiota has been implicated in the regulation of tumor progression and therapeutic efficacy. However, the effect of microbiota on disease progression is context dependent, differing according to tumor types, therapeutic regimens, and composition of the microbiota, calling for a deeper understanding of host-microbiome interactions. Previous studies have demonstrated that gut microbiota influences disease progression by regulating local and systemic immunity. Notably, with the advent of next-generation sequencing technology, intratumoral microbiota has also been found and constitutes an important component of the tumor microenvironment. In this review, we summarize recent knowledge about the identification of intra-tumor microbiota and discuss the role of gut and intratumoral microbiota in solid tumors in the angle of immune microenvironment interaction. Furthermore, we discuss how these findings may benefit current anti-cancer approaches. Key problems to be solved in ongoing and future research are highlighted.

2.
Oncogene ; 40(29): 4737-4745, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34188249

RESUMO

B cells constitute a major component of tumor-infiltrating leukocytes. However, the influence of these cells on malignancy is currently under debate, reflecting the heterogeneity of B cell subsets in tumors. With recent advances, it becomes apparent that this debate includes not only the evaluation of B cells themselves, but also the underlying immune microenvironment network, which scripts the highly heterogeneous B cell populations in tumors and directs the roles of those sub-populations in disease progression and clinical treatment. In this review, we summarize recent findings on the heterogeneous subset composition of B cells in both human and mouse tumor models and their different impacts on disease progression. We further describe the multidimensional interplays between B cells and other immune cells in the tumor microenvironment, which account for the regulation of B cell differentiation and function in situ. We also assess the potential influences of distinct sub-tumor locations on B cell function in primary tumors during development and those under immunotherapy treatment. Illuminating the heterogeneous nature of B cell subset composition, generation, localization, and related immune network in tumor is of immense significance for comprehensively understanding B cell response in tumor and designing more efficacious cancer immunotherapies.

4.
Cell Mol Life Sci ; 78(3): 867-887, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32940722

RESUMO

PD-1/PD-L1 axis represents an important target for renormalizing and resetting anti-tumor immunity in cancer patients. Currently, anti-PD-1/PD-L1 therapy has been applied in a broad spectrum of tumors and has yielded durable remission in patients. However, how to further broaden the application, guide personalized therapeutic strategies, and improve clinical responses remains a vital task. At present, PD-L1 expression is an important parameter of clinical indications for immune checkpoint blockade in many types of cancers, a strategy based on the supposition that positive PD-L1 expression reflects local T cell response. Recent studies have revealed that PD-L1 expression is regulated by multiple layers of complicated factors, during which the host immune microenvironment exerts a pivotal role and determines the clinical efficacy of the therapy. In this review, we will summarize recent findings on PD-1/PD-L1 in cancer, focusing on how local immune landscape participates in the regulation of PD-L1 expression and modification. Importantly, we will also discuss these topics in the context of clinical treatment and analyze how these fundamental principles might inspire our efforts to develop more precise and effective immune therapeutics for cancer.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias/patologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/imunologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral
5.
Sci Adv ; 6(37)2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32917682

RESUMO

B cells constitute abundant cellular components in inflamed human tissues, but their role in pathogenesis of inflammatory T helper (TH) subsets is still unclear. Here, we demonstrate that B cells, particularly resting naïve B cells, have a previously unrecognized helper function that is involved in shaping the metabolic process and subsequent inflammatory differentiation of T-cell receptor-primed TH cells. ICOS/ICOSL axis-mediated glucose incorporation and utilization were crucial for inflammatory TH subset induction by B cells, and activation of mTOR was critical for T cell glycolysis in this process. Consistently, upon encountering ICOSL+ B cells, activated effector memory TH cells from patients with rheumatoid arthritis or systemic lupus erythematosus spontaneously differentiated into inflammatory TH subsets. Immunotherapy using rituximab that specifically depleted B cells in patients with rheumatoid arthritis efficiently abrogated the capabilities of memory TH cells to incorporate and use glucose, thereby impairing the pathogenic differentiation of inflammatory TH subsets.

6.
Cell Res ; 30(11): 1024-1042, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32686767

RESUMO

Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with extremely skewed ethnic and geographic distributions. Increasing evidence indicates that targeting the tumor microenvironment (TME) represents a promising therapeutic approach in NPC, highlighting an urgent need to deepen the understanding of the complex NPC TME. Here, we generated single-cell transcriptome profiles for 7581 malignant cells and 40,285 immune cells from fifteen primary NPC tumors and one normal sample. We revealed malignant signatures capturing intratumoral transcriptional heterogeneity and predicting aggressiveness of malignant cells. Diverse immune cell subtypes were identified, including novel subtypes such as CLEC9A+ dendritic cells (DCs). We further revealed transcriptional regulators underlying immune cell diversity, and cell-cell interaction analyses highlighted promising immunotherapeutic targets in NPC. Moreover, we established the immune subtype-specific signatures, and demonstrated that the signatures of macrophages, plasmacytoid dendritic cells (pDCs), CLEC9A+ DCs, natural killer (NK) cells, and plasma cells were significantly associated with improved survival outcomes in NPC. Taken together, our findings represent a unique resource providing in-depth insights into the cellular heterogeneity of NPC TME and highlight potential biomarkers for anticancer treatment and risk stratification, laying a new foundation for precision therapies in NPC.


Assuntos
Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/imunologia , Análise de Célula Única , Transcriptoma/genética , Linfócitos B/imunologia , Comunicação Celular , Diferenciação Celular , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade , Células Matadoras Naturais/imunologia , Macrófagos/metabolismo , Monócitos/metabolismo , Células Mieloides/metabolismo , Carcinoma Nasofaríngeo/patologia , Fenótipo , Prognóstico , Processos Estocásticos , Análise de Sobrevida , Linfócitos T/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
7.
Cancer Res ; 80(4): 675-688, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31948940

RESUMO

Suppression of gluconeogenesis elevates glycolysis and is commonly observed in tumors derived from gluconeogenic tissues including liver and kidney, yet the definitive regulatory mechanism remains elusive. Here, we screened an array of transcription regulators and identified the enhancer of zeste homolog 2 (EZH2) as a key factor that inhibits gluconeogenesis in cancer cells. Specifically, EZH2 repressed the expression of a rate-limiting gluconeogenic enzyme fructose-1, 6-bisphosphatase 1 (FBP1) and promoted tumor growth primarily through FBP1 suppression. Furthermore, EZH2 was upregulated by genotoxins that commonly induce hepatic and renal tumorigenesis. Genotoxin treatments augmented EZH2 acetylation, leading to reduced association between EZH2 and its E3 ubiquitin ligase SMURF2. Consequently, EZH2 became less ubiquitinated and more stabilized, promoting FBP1 attenuation and tumor formation. Intriguingly, FBP1 physically interacted with EZH2, competed for EZH2 binding, and dissembled the polycomb complex. Therefore, FBP1 suppresses polycomb-initiated transcriptional responses and constitutes a double-negative feedback loop indispensable for EZH2-promoted tumorigenesis. Finally, EZH2 and FBP1 levels were inversely correlated in tumor tissues and accurately predicted patient survival. This work reveals an unexpected cross-talk between epigenetic and metabolic events, and identifies a new feedback circuitry that highlights EZH2 inhibitors as liver and kidney cancer therapeutics. SIGNIFICANCE: A novel feedback loop involving EZH2 and suppression of the gluconeogenesis enzyme FBP1 promotes hepatocellular cancer growth.See related commentary by Leithner, p. 657.


Assuntos
Gluconeogênese , Neoplasias Renais/genética , Carcinogênese , Linhagem Celular Tumoral , Proteína Potenciadora do Homólogo 2 de Zeste , Epigênese Genética , Frutose , Regulação Neoplásica da Expressão Gênica , Humanos
8.
J Clin Invest ; 129(8): 3347-3360, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31112529

RESUMO

PD-L1 is a promising therapeutic target in aggressive cancers. However, immune landscapes and cancer hallmarks of human PD-L1+ tumors, as well as their roles in determining therapeutic efficacies are unknown. Here we identified, in detailed studies of gene data regarding 9769 patients of 32 types of human cancers, that PD-L1 could not exclusively represent IFN-γ signature and potentially signified pro-inflammatory myeloid responses in a tumor. PD-L1 heterogeneity endowed by local immune landscapes controlled cancer hallmarks and clinical outcomes of patients. Mechanically, NF-κB signal elicited by macrophage inflammatory responses generated PD-L1+ cancer cells exhibiting capabilities to aggressively survive, support angiogenesis, and metastasize, whereas STAT1 signal triggered by activated T cells induced PD-L1+ cancer cells susceptive to apoptosis. Importantly, PD-L1+ cancer cells generated by macrophages established great resistance to conventional chemotherapy, cytotoxicity of tumor-specific effector T cells, and therapy of immune checkpoint blockade. Therapeutic strategy combining immune checkpoint blockade with macrophage depletion or NF-κB inhibition in vivo effectively and successfully elicited caner regression. Our results provide insight into the functional features of PD-L1+ tumors and suggest that strategies to influence functional activities of inflammatory cells may benefit immune checkpoint blockade therapy.


Assuntos
Antígeno B7-H1/imunologia , Imunoterapia , Macrófagos/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias , Linfócitos T , Adolescente , Adulto , Idoso , Animais , Feminino , Células Hep G2 , Humanos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Linfócitos T/imunologia , Linfócitos T/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Hepatol ; 71(2): 333-343, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071366

RESUMO

BACKGROUND & AIMS: Programmed cell death 1 ligand 1 (PD-L1) expression on antigen-presenting cells is essential for T cell impairment, and PD-L1-expressing macrophages may mechanistically shape and therapeutically predict the clinical efficacy of PD-L1 or programmed cell death 1 blockade. We aimed to elucidate the mechanisms underlying PD-L1 upregulation in human tumor microenvironments, which remain poorly understood despite the clinical success of immune checkpoint inhibitors. METHODS: Monocytes/macrophages were purified from peripheral blood, non-tumor, or paired tumor tissues of patients with hepatocellular carcinoma (HCC), and their possible glycolytic switch was evaluated. The underlying regulatory mechanisms and clinical significance of metabolic switching were studied with both ex vivo analyses and in vitro experiments. RESULTS: We found that monocytes significantly enhanced the levels of glycolysis at the peritumoral region of human HCC. The activation of glycolysis induced PD-L1 expression on these cells and subsequently attenuated cytotoxic T lymphocyte responses in tumor tissues. Mechanistically, tumor-derived soluble factors, including hyaluronan fragments, induced the upregulation of a key glycolytic enzyme, PFKFB3, in tumor-associated monocytes. This enzyme not only modulated the cellular metabolic switch but also mediated the increased expression of PD-L1 by activating the nuclear factor kappa B signaling pathway in these cells. Consistently, the levels of PFKFB3+CD68+ cell infiltration in peritumoral tissues were negatively correlated with overall survival and could serve as an independent prognostic factor for survival in patients with HCC. CONCLUSIONS: Our results reveal a mechanism by which the cellular metabolic switch regulates the pro-tumor functions of monocytes in a specific human tumor microenvironment. PFKFB3 in both cancer cells and tumor-associated monocytes is a potential therapeutic target in human HCC. LAY SUMMARY: Programmed cell death 1 ligand 1 (PD-L1) expressed on antigen-presenting cells, rather than tumor cells, has been reported to play an essential role in checkpoint blockade therapy. A fundamental understanding of mechanisms that regulate the expression of PD-L1 on tumor-infiltrating monocytes/macrophages will undoubtedly lead to the possibility of developing novel PD-L1 blockade strategies with high specificity and efficiency. The current study unveils a novel mechanism by which metabolic switching links immune activation responses to immune tolerance in the tumor milieu, identifying potential targets for future immune-based anti-cancer therapies.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/imunologia , Glicólise , Privilégio Imunológico , Neoplasias Hepáticas/imunologia , Monócitos/metabolismo , Fosfofrutoquinase-2/metabolismo , Adulto , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/patologia , Progressão da Doença , Feminino , Seguimentos , Células Hep G2 , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/patologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Microambiente Tumoral/imunologia , Adulto Jovem
10.
Gastroenterology ; 156(6): 1890-1904.e16, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30711627

RESUMO

BACKGROUND & AIMS: Little is known about the composition and generation of plasma cell subsets in patients with hepatocellular carcinoma (HCC) and how these associate with outcomes. We investigated whether, or how, plasma cells differentiate and function in patients with HCC and mice with liver tumors. METHODS: We analyzed subset composition and distribution of plasma cells in HCC samples from 342 patients who underwent curative resection at the Cancer Center of Sun Yat-sen University in China; samples of non-tumor liver tissue were used as controls. We associated plasma cell profiles with patient outcomes. Tissue-derived leukocytes were analyzed by flow cytometry and real-time polymerase chain reaction. The ability of macrophages to regulate plasma cell differentiation was determined in ex vivo cultures of cells from human HCC tissues. C57BL/6 and BALB/c mice were given injections of Hepa1-6 cells, which formed hepatomas, or H22 cells, which formed ascitic hepatomas. Gene expression patterns were analyzed in human HCC, mouse hepatoma, and non-tumor tissues by real-time polymerase chain reaction. Mice with hepatomas were given injections of GSK126 (an inhibitor of histone H3 lysine 27 methyltransferase [EZH2]) and 5-AZA-dC (an inhibitor of DNA methyltransferases); tumor tissues were analyzed by immunofluorescence and immunohistochemistry for the presence of immune cells and cytokines. RESULTS: B cells isolated from HCCs had somatic hypermutations and class-switch recombinations to the IgG phenotype that were not observed in non-tumor tissues. Increased level of plasma cells correlated with poor outcomes of patients. Activated CD4+ T cells from HCCs stimulated C-X-C motif chemokine 10 (CXCL10) production by macrophages. CXCL10 bound CXC chemokine receptor 3 on B cells and signaled via extracellular signal-regulated kinase to cause them to become IgG-producing plasma cells. IgG activated Fc receptors on macrophages and induced them to produce interleukin 6, interleukin 10, and C-C motif chemokine ligand 20 (CCL20). In mice with hepatomas, depletion of B cells prevented generation of these macrophage, increased the anti-tumor T cell response, and reduced growth of hepatomas. However, these effects were lost after injection of CXC chemokine receptor 3-positive plasma cells. Human HCC and mouse hepatoma tissues had increased expression of DNA methyltransferase 1 and EZH2 compared with non-tumor tissues. Injection of mice with GSK126 and 5-AZA-dC induced expression of CXCL10 by tumor cells and caused plasma cell polarization, suppression of the anti-tumor T cell response, and hepatoma growth. CONCLUSIONS: Human HCC tissues contain B cells with class-switch recombinations to the IgG phenotype. Activated CD4+ T cells from HCCs stimulate CXCL10 production by macrophages; CXCL10 binds CXC chemokine receptor 3 on B cells and causes them to become IgG-producing plasma cells. IgG activates Fc receptor in macrophages to produce cytokines that reduce the anti-tumor immune response. In mice with hepatomas, depletion of B cells prevented generation of these macrophages, increased the anti-tumor T cell response, and reduced growth of hepatomas. This pathway involves increased expression of DNA methyltransferase 1 and EZH2 by HCC and hepatoma cells.


Assuntos
Carcinoma Hepatocelular/genética , Epigênese Genética , Imunoglobulina G/metabolismo , Neoplasias Hepáticas/genética , Macrófagos/metabolismo , Plasmócitos/metabolismo , Adulto , Idoso , Animais , Antimetabólitos Antineoplásicos/farmacologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Quimiocina CCL20/metabolismo , Quimiocina CXCL10/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Decitabina/farmacologia , Progressão da Doença , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Indóis/farmacologia , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Fígado/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Contagem de Linfócitos , Masculino , Camundongos , Pessoa de Meia-Idade , Transplante de Neoplasias , Fenótipo , Plasmócitos/imunologia , Piridonas/farmacologia , Receptores CXCR3/metabolismo , Receptores Fc/metabolismo , Transdução de Sinais , Transcriptoma
11.
Nat Commun ; 7: 13453, 2016 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-27853178

RESUMO

B cells are prominent components of human solid tumours, but activation status and functions of these cells in human cancers remain elusive. Here we establish that over 50% B cells in hepatocellular carcinoma (HCC) exhibit an FcγRIIlow/- activated phenotype, and high infiltration of these cells positively correlates with cancer progression. Environmental semimature dendritic cells, but not macrophages, can operate in a CD95L-dependent pathway to generate FcγRIIlow/- activated B cells. Early activation of monocytes in cancer environments is critical for the generation of semimature dendritic cells and subsequent FcγRIIlow/- activated B cells. More importantly, the activated FcγRIIlow/- B cells from HCC tumours, but not the resting FcγRIIhigh B cells, without external stimulation suppress autologous tumour-specific cytotoxic T-cell immunity via IL-10 signals. Collectively, generation of FcγRIIlow/- activated B cells may represent a mechanism by which the immune activation is linked to immune tolerance in the tumour milieu.


Assuntos
Linfócitos B/fisiologia , Carcinoma Hepatocelular/imunologia , Privilégio Imunológico/fisiologia , Interleucina-10/metabolismo , Neoplasias Hepáticas/imunologia , Ativação Linfocitária/fisiologia , Proteína Ligante Fas/genética , Proteína Ligante Fas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Gravidez , Receptor fas/genética , Receptor fas/metabolismo
12.
Oncoimmunology ; 5(10): e1219828, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27853643

RESUMO

Inflammation is a component of tumor progression mechanisms. Neutrophils are a common inflammatory infiltrate in many tumors, but their regulation and functions in neoplasia are not understood. Here, we showed, in detailed studies of c-Met molecule in 225 untreated patients with hepatocellular carcinoma (HCC), that high infiltration of neutrophils in HCC tissues determined malignant cell c-Met-associated clinical outcome of patients. High infiltration of neutrophils in HCCs determined malignant cell c-Met-associated clinical outcome of patients. Neutrophils were enriched predominantly in invading tumor edge of HCCs; the accumulated neutrophils were the major source of c-Met ligand HGF in HCCs. Exposure to HCC environments resulted in neutrophil activation and the following HGF production. Inhibiting the activities of Erk1/2, p38, and NF-κB, but not the phosphorylation of AKT or JNK, successfully attenuated the neutrophil HGF production induced by HCC environments. Further investigation revealed that GM-CSF was an important determinant in malignant cell-elicited neutrophil HGF production in vitro and in vivo. Moreover, we demonstrated that tumor neutrophils, via HGF/c-Met interaction, actively enhanced the metastasis of malignant cells in vitro and in vivo. These data provide direct evidence supporting the critical role of neutrophils in human tumor progression and reveal a fine-tuned collaborative action between cancer cells and immune cells in tumor milieu, which reroutes the immune activation into a tumor-promoting direction.

13.
Cancer Discov ; 6(10): 1182-1195, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27531854

RESUMO

The existence, regulation, and functions of IL21+ immune cells are poorly defined in human cancers. Here, we identified a subset of protumorigenic IL21+ TFH-like cells in human hepatocellular carcinoma. These cells were the major source of IL21 in tumors and represented about 10% of the CD4+ T-cell population at levels comparable with the TFH cells present in lymph nodes. However, these TFH-like cells displayed a unique CXCR5-PD-1lo/-BTLA-CD69hi tissue-resident phenotype with substantial IFNγ production, which differed from the phenotype of TFH cells. Toll-like receptor 4 (TLR4)-elicited innate monocyte inflammation was important for IL21+ TFH-like cell induction in tumors, and activation of STAT1 and STAT3 was critical for TFH-like cell polarization in this process. Importantly, the TFH-like cells operated in IL21-IFNγ-dependent pathways to induce plasma cell differentiation and thereby create conditions for protumorigenic M2b macrophage polarization and cancer progression. Thus, induction of TFH-like cells links innate inflammation to immune privilege in tumors. SIGNIFICANCE: We identified a novel protumorigenic IL21+ TFH-like cell subset with a CXCR5-PD-1- BTLA-CD69hi tissue-resident phenotype in hepatoma. TLR4-mediated monocyte inflammation and subsequent T-cell STAT1 and STAT3 activation are critical for TFH-like cell induction. TFH-like cells operate via IL21-IFNγ pathways to induce plasma cells and create conditions for M2b macrophage polarization. Cancer Discov; 6(10); 1182-95. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1069.


Assuntos
Carcinoma Hepatocelular/imunologia , Inflamação/metabolismo , Interleucinas/metabolismo , Macrófagos/fisiologia , Monócitos/imunologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Polaridade Celular , Humanos , Interferon gama/metabolismo , Neoplasias Hepáticas , Receptor 4 Toll-Like/metabolismo
14.
Cancer Discov ; 6(5): 546-59, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26928313

RESUMO

UNLABELLED: B cells often constitute abundant cellular components in human tumors. Regulatory B cells that are functionally defined by their ability to produce IL10 downregulate inflammation and control T-cell immunity. Here, we identified a protumorigenic subset of B cells that constitutively expressed higher levels of programmed cell death-1 (PD-1) and constituted ∼10% of all B cells in advanced-stage hepatocellular carcinoma (HCC). These PD-1(hi) B cells exhibited a unique CD5(hi)CD24(-/+)CD27(hi/+)CD38(dim) phenotype different from the phenotype of conventional CD24(hi)CD38(hi) peripheral regulatory B cells. TLR4-mediated BCL6 upregulation was crucial for PD-1(hi) B-cell induction by HCC environmental factors, and that effect was abolished by IL4-elicited STAT6 phosphorylation. Importantly, upon encountering PD-L1(+) cells or undergoing PD-1 triggering, PD-1(hi) B cells acquired regulatory functions that suppressed tumor-specific T-cell immunity and promoted cancer growth via IL10 signals. Our findings provide significant new insights for human cancer immunosuppression and anticancer therapies regarding PD-1/PD-L1. SIGNIFICANCE: We identify a novel protumorigenic PD-1(hi) B-cell subset in human HCC that exhibits a phenotype distinct from that of peripheral regulatory B cells. TLR4-mediated BCL6 upregulation is critical for induction of PD-1(hi) B cells, which operate via IL10-dependent pathways upon interacting with PD-L1 to cause T-cell dysfunction and foster disease progression. Cancer Discov; 6(5); 546-59. ©2016 AACR.See related commentary by Ren et al., p. 477This article is highlighted in the In This Issue feature, p. 461.


Assuntos
Linfócitos B Reguladores/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Receptor de Morte Celular Programada 1/metabolismo , Animais , Linfócitos B Reguladores/imunologia , Antígeno B7-H1/metabolismo , Biomarcadores , Carcinoma Hepatocelular/etiologia , Linhagem Celular Tumoral , Citocinas/biossíntese , Modelos Animais de Doenças , Progressão da Doença , Citometria de Fluxo , Expressão Gênica , Hepatite B , Hepatite C , Xenoenxertos , Humanos , Imunomodulação , Imunofenotipagem , Neoplasias Hepáticas/etiologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Estadiamento de Neoplasias , Fenótipo , Receptor de Morte Celular Programada 1/genética , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Recidiva , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais
15.
Oncoimmunology ; 5(12): e1254855, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28123898

RESUMO

Although immunotherapy targeting programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway is being applied in clinic, the response outcomes are heterogeneous, suggesting existences of distinctive subsets within PD-1-expressing T cells that react differently to PD-1/PD-L1 blockade. However, markers to demarcate these subsets in human cancers remain unclear. Here, we found that both PD-1 and B and T lymphocyte attenuator (BTLA) were significantly upregulated on CD4+ T cells from tumor compared with those from paired non-tumor liver in hepatocellular carcinoma (HCC) patients. Interestingly, over 85% BTLA+ CD4+ T cells were PD-1-expressing cells and represented about 50% PD-1+ CD4+ T cells in tumors, and that level of BTLA+PD-1+ tumor CD4+ T cells were selectively associated with advanced stage HCC. BTLA+ identified highly dysfunctional PD-1-expressing CD4+ T cell subset, whereas BTLA- defined PD-1+ CD4+ T cells undergoing activation in HCC. Importantly, blockade of PD-L1 could restore the ability of IFNγ/TNF-α production in BTLA+PD-1+ tumor CD4+ T cells but partially suppressed the activation of BTLA-PD-1+ CD4+ T cells. Moreover, we provided evidence that BTLA signals also participated in suppressing CD4+ T cell function in HCC. In conclusion, BTLA could identify distinct function of PD-1 expressing CD4+ T cells in human cancer, which might not only advance our understanding of inhibitory receptor blockade, but also provide new targets for clinical predictors of response to these immunotherapies.

16.
Hepatology ; 62(6): 1779-90, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26235097

RESUMO

UNLABELLED: B cells consistently represent abundant cellular components in tumors; however, direct evidence supporting a role for B cells in the immunopathogenesis of human cancers is lacking, as is specific knowledge of their trafficking mechanisms. Here, we demonstrate that chemokine (C-X-C motif) receptor 3-positive (CXCR3(+)) B cells constitute approximately 45% of B-cell infiltrate in human hepatocellular carcinoma (HCC) and that their levels are positively correlated with early recurrence of HCC. These cells selectively accumulate at the invading edge of HCC and undergo further somatic hypermutation and immunoglobulin G-secreting plasma cell differentiation. Proinflammatory interleukin-17(+) cells are important for the induction of epithelial cell-derived CXCR3 ligands CXCL9, CXCL10, and CXCL11, which subsequently promote the sequential recruitment and further maturation of CXCR3(+) B cells. More importantly, we provide evidence that CXCR3(+) B cells, but not their CXCR3(-) counterparts, may operate in immunoglobulin G-dependent pathways to induce M2b macrophage polarization in human HCC. Depletion of B cells significantly suppresses M2b polarization and the protumorigenic activity of tumor-associated macrophages and restores the production of antitumorigenic interleukin-12 by those cells in vivo. CONCLUSION: Selective recruitment of CXCR3(+) B cells bridges proinflammatory interleukin-17 response and protumorigenic macrophage polarization in the tumor milieu, and blocking CXCR3(+) B-cell migration or function may help defeat HCC.


Assuntos
Linfócitos B/fisiologia , Carcinoma Hepatocelular/imunologia , Inflamação/imunologia , Interleucina-17/fisiologia , Neoplasias Hepáticas/imunologia , Macrófagos/fisiologia , Receptores CXCR3/fisiologia , Animais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL
17.
J Hepatol ; 62(1): 131-9, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25152203

RESUMO

BACKGROUND & AIMS: Neutrophils are common cells of the inflammatory infiltrate and are predominantly enriched in many cancers. We recently found that neutrophils are accumulated in human hepatocellular carcinoma (HCC), where they promote disease progression by releasing matrix metalloproteinase-9 (MMP9). The underlying mechanisms, however, that allow tumour microenvironments to educate neutrophils are largely unknown. METHODS: Neutrophils were purified from HCC patients and healthy donors. Immunohistochemistry and immunoblotting were used for the evaluation of autophagy in neutrophils. The regulation and function of increased neutrophil autophagy were assessed by both in vitro and ex vivo studies. RESULTS: Most neutrophils in HCC intratumoural regions, in contrast to those located in the paired non-tumoural areas and within tumour vessels, substantially expressed autophagy-specific protein LC3. Soluble factors derived from hepatoma, including hyaluronan fragments, triggered a considerable increase of functional LC3 and autophagosomes in neutrophils, but this was unrelated to the deactivation of mTOR signalling. Inhibiting the activation of Erk1/2, p38, and NF-κB signals could significantly attenuate such tumour-elicited autophagy. These neutrophils, undergoing autophagy, exhibited long-lived phenotypes with retained Mcl-1 and significantly more intact mitochondria as well as low cleaved caspase-3, which could be abolished by inhibiting the initiation of autophagy. Moreover, increased neutrophil autophagy also correlated with sustained production of pro-metastatic oncostatin M and MMP9 and advanced migration of cancer cells. CONCLUSIONS: Increased autophagy in neutrophils may represent a novel mechanism that links the innate response to neoplastic progression in humans. Studying the mechanisms that selectively modulate neutrophil autophagy will provide a novel strategy for anti-cancer therapy.


Assuntos
Autofagia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Neutrófilos/ultraestrutura , Adulto , Idoso , Apoptose , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Immunoblotting , Neoplasias Hepáticas/metabolismo , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Transdução de Sinais
18.
J Clin Invest ; 124(10): 4657-67, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25244097

RESUMO

Classical IL-22-producing T helper cells (Th22 cells) mediate inflammatory responses independently of IFN-γ and IL-17; however, nonclassical Th22 cells have been recently identified and coexpress IFN-γ and/or IL-17 along with IL-22. Little is known about how classical and nonclassical Th22 subsets in human diseases are regulated. Here, we used samples of human blood, normal and peritumoral liver, and hepatocellular carcinoma (HCC) to delineate the phenotype, distribution, generation, and functional relevance of various Th22 subsets. Three nonclassical Th22 subsets constituted the majority of all Th22 cells in human liver and HCC tissues, although the classical Th22 subset was predominant in blood. Monocytes activated by TLR2 and TLR4 agonists served as the antigen-presenting cells (APCs) that most efficiently triggered the expansion of nonclassical Th22 subsets from memory T cells and classical Th22 subsets from naive T cells. Moreover, B7-H1-expressing monocytes skewed Th22 polarization away from IFN-γ and toward IL-17 through interaction with programmed death 1 (PD-1), an effect that can create favorable conditions for in vivo aggressive cancer growth and angiogenesis. Our results provide insight into the selective modulation of Th22 subsets and suggest that strategies to influence functional activities of inflammatory cells may benefit anticancer therapy.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Antígeno B7-H1/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Animais , Carcinoma Hepatocelular/metabolismo , Separação Celular , Citometria de Fluxo , Células HEK293 , Células Hep G2 , Humanos , Inflamação , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucinas/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Monócitos/citologia , Transplante de Neoplasias , Fenótipo
19.
Hepatology ; 57(3): 1107-16, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23225218

RESUMO

UNLABELLED: Defects in natural killer (NK) cell functions are necessary for tumor immune escape, but their underlying regulatory mechanisms in human cancers remain largely unknown. Here we show, in detailed studies of NK cells in 294 untreated patients with hepatocellular carcinoma (HCC), that accumulation of functional NK cells in HCC tissues could predict improved survival of patients. However, in patients with advanced-stage HCC, NK cells were significantly decreased in number with impaired tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ) production. High infiltration of peritumoral stroma monocytes/macrophages was positively correlated with impaired functional activities of NK cells in intratumoral areas. Further kinetic experiments revealed that soon after exposure to tumor-derived monocytes, NK cells underwent a rapid, transient activation, but then they became exhausted, and eventually died. The monocytes from HCC tissues, but not from nontumoral liver, strongly express CD48 proteins; and such monocyte-induced NK cell dysfunction was markedly attenuated by blocking CD48 receptor 2B4 on NK cells, but not by blockade of NKG2D and NKp30. CONCLUSION: These data reveal that human NK cells are regulated by a fine-tuned collaborative action between different types of immune cells, which may reflect a novel immune-escape mechanism by which tumors dynamically regulate their functions at distinct tumor microenvironments.


Assuntos
Antígenos CD/imunologia , Carcinoma Hepatocelular/imunologia , Células Matadoras Naturais/imunologia , Neoplasias Hepáticas/imunologia , Monócitos/imunologia , Receptores Imunológicos/imunologia , Antígenos CD/metabolismo , Apoptose/imunologia , Antígeno CD48 , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Comunicação Celular/imunologia , Sobrevivência Celular/imunologia , Feminino , Humanos , Interferon gama/metabolismo , Células Matadoras Naturais/metabolismo , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Receptores Imunológicos/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária , Microambiente Tumoral/imunologia , Fator de Necrose Tumoral alfa/metabolismo
20.
J Immunol ; 188(3): 1117-24, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22184722

RESUMO

Substantial evidence indicates that immune activation at stroma can be rerouted in a tumor-promoting direction. CD69 is an immunoregulatory molecule expressed by early-activated leukocytes at sites of chronic inflammation, and CD69(+) T cells have been found to promote human tumor progression. In this study, we showed that, upon encountering autologous CD69(+) T cells, tumor macrophages (MΦs) acquired the ability to produce much greater amounts of IDO protein in cancer nests. The T cells isolated from the hepatocellular carcinoma tissues expressed significantly more CD69 molecules than did those on paired circulating and nontumor-infiltrating T cells; these tumor-derived CD69(+) T cells could induce considerable IDO in monocytes. Interestingly, the tumor-associated monocytes/MΦs isolated from hepatocellular carcinoma tissues or generated by in vitro culture effectively activated circulating T cells to express CD69. IL-12 derived from tumor MΦs was required for early T cell activation and subsequent IDO expression. Moreover, we found that conditioned medium from IDO(+) MΦs effectively suppressed T cell responses in vitro, an effect that could be reversed by adding extrinsic IDO substrate tryptophan or by pretreating MΦs with an IDO inhibitor 1-methyl-DL-tryptophan. These data revealed a fine-tuned collaborative action between different types of immune cells to counteract T cell responses in tumor microenvironment. Such an active induction of immune tolerance should be considered for the rational design of effective immune-based anticancer therapies.


Assuntos
Antígenos CD , Antígenos de Diferenciação de Linfócitos T , Carcinoma Hepatocelular/imunologia , Tolerância Imunológica , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Lectinas Tipo C , Macrófagos/metabolismo , Linfócitos T/imunologia , Humanos , Ativação Linfocitária , Triptofano
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