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1.
Immunity ; 56(1): 180-192.e11, 2023 01 10.
Article in English | MEDLINE | ID: mdl-36563676

ABSTRACT

The reinvigoration of anti-tumor T cells in response to immune checkpoint blockade (ICB) therapy is well established. Whether and how ICB therapy manipulates antibody-mediated immune response in cancer environments, however, remains elusive. Using tandem mass spectrometric analysis of modification of immunoglobulin G (IgG) from hepatoma tissues, we identified a role of ICB therapy in catalyzing IgG sialylation in the Fc region. Effector T cells triggered sialylation of IgG via an interferon (IFN)-γ-ST6Gal-I-dependent pathway. DC-SIGN+ macrophages represented the main target cells of sialylated IgG. Upon interacting with sialylated IgG, DC-SIGN stimulated Raf-1-elicited elevation of ATF3, which inactivated cGAS-STING pathway and eliminated subsequent type-I-IFN-triggered antitumorigenic immunity. Although enhanced IgG sialylation in tumors predicted improved therapeutic outcomes for patients receiving ICB therapy, impeding IgG sialylation augmented antitumorigenic T cell immunity after ICB therapy. Thus, targeting antibody-based negative feedback action of ICB therapy has potential for improving efficacy of cancer immunotherapies.


Subject(s)
Carcinoma, Hepatocellular , Interferon Type I , Liver Neoplasms , Humans , Immunoglobulin G , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Immunotherapy/methods
2.
Gastroenterology ; 166(6): 1069-1084, 2024 06.
Article in English | MEDLINE | ID: mdl-38445519

ABSTRACT

BACKGROUND & AIMS: Although the presence of tertiary lymphoid structures (TLS) correlates with positive responses to immunotherapy in many solid malignancies, the mechanism by which TLS enhances antitumor immunity is not well understood. The present study aimed to investigate the underlying cross talk circuits between B cells and tissue-resident memory T (Trm) cells within the TLS and to understand their role in the context of immunotherapy. METHODS: Immunostaining and H&E staining of TLS and chemokine (C-X-C motif) ligand 13 (CXCL13)+ cluster of differentiation (CD)103+CD8+ Trm cells were performed on tumor sections from patients with gastric cancer (GC). The mechanism of communication between B cells and CXCL13+CD103+CD8+ Trm cells was determined in vitro and in vivo. The effect of CXCL13+CD103+CD8+ Trm cells in suppressing tumor growth was evaluated through anti-programmed cell death protein (PD)-1 therapy. RESULTS: The presence of TLS and CXCL13+CD103+CD8+ Trm cells in tumor tissues favored a superior response to anti-PD-1 therapy in patients with GC. Additionally, our research identified that activated B cells enhanced CXCL13 and granzyme B secretion by CD103+CD8+ Trm cells. Mechanistically, B cells facilitated the glycolysis of CD103+CD8+ Trm cells through the lymphotoxin-α/tumor necrosis factor receptor 2 (TNFR2) axis, and the mechanistic target of rapamycin signaling pathway played a critical role in CD103+CD8+ Trm cells glycolysis during this process. Moreover, the presence of TLS and CXCL13+CD103+CD8+ Trm cells correlated with potent responsiveness to anti-PD-1 therapy in a TNFR2-dependent manner. CONCLUSIONS: This study further reveals a crucial role for cellular communication between TLS-associated B cell and CXCL13+CD103+CD8+ Trm cells in antitumor immunity, providing valuable insights into the potential use of the lymphotoxin-α/TNFR2 axis within CXCL13+CD103+CD8+ Trm cells for advancing immunotherapy strategies in GC.


Subject(s)
Antigens, CD , B-Lymphocytes , CD8-Positive T-Lymphocytes , Chemokine CXCL13 , Immune Checkpoint Inhibitors , Integrin alpha Chains , Memory T Cells , Programmed Cell Death 1 Receptor , Stomach Neoplasms , Tertiary Lymphoid Structures , Chemokine CXCL13/metabolism , Humans , Tertiary Lymphoid Structures/immunology , Tertiary Lymphoid Structures/pathology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , B-Lymphocytes/drug effects , Stomach Neoplasms/immunology , Stomach Neoplasms/pathology , Stomach Neoplasms/therapy , Stomach Neoplasms/drug therapy , Antigens, CD/metabolism , Integrin alpha Chains/metabolism , Integrin alpha Chains/immunology , Memory T Cells/immunology , Memory T Cells/metabolism , Animals , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Granzymes/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphocytes, Tumor-Infiltrating/drug effects , Immunologic Memory , Signal Transduction/immunology , Tumor Microenvironment/immunology , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , Mice , Immunotherapy/methods , Cell Line, Tumor
3.
Gastroenterology ; 166(3): 466-482, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38065340

ABSTRACT

BACKGROUND & AIMS: Although immunotherapy shows substantial advancement in colorectal cancer (CRC) with microsatellite instability high, it has limited efficacy for CRC with microsatellite stability (MSS). Identifying combinations that reverse immune suppression and prime MSS tumors for current immunotherapy approaches remains an urgent need. METHODS: An in vitro CRISPR screen was performed using coculture models of primary tumor cells and autologous immune cells from MSS CRC patients to identify epigenetic targets that could enhance immunotherapy efficacy in MSS tumors. RESULTS: We revealed EHMT2, a histone methyltransferase, as a potential target for MSS CRC. EHMT2 inhibition transformed the immunosuppressive microenvironment of MSS tumors into an immunomodulatory one by altering cytokine expression, leading to T-cell-mediated cytotoxicity activation and improved responsiveness to anti-PD1 treatment. We observed galectin-7 up-regulation upon EHMT2 inhibition, which converted a "cold" MSS tumor environment into a T-cell-inflamed one. Mechanistically, CHD4 repressed galectin-7 expression by recruiting EHMT2 to form a cotranscriptional silencing complex. Galectin-7 administration enhanced anti-PD1 efficacy in MSS CRC, serving as a potent adjunct cytokine therapy. CONCLUSIONS: Our findings suggest that targeting the EHMT2/galectin-7 axis could provide a novel combination strategy for immunotherapy in MSS CRC.


Subject(s)
Colorectal Neoplasms , Humans , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Immunotherapy , Cytokines , Galectins/genetics , Microsatellite Repeats , Microsatellite Instability , Tumor Microenvironment , Histocompatibility Antigens , Histone-Lysine N-Methyltransferase
4.
Hepatology ; 2024 Mar 27.
Article in English | MEDLINE | ID: mdl-38537134

ABSTRACT

BACKGROUND AND AIMS: HBV infection is a major etiology of acute-on-chronic liver failure (ACLF). At present, the pattern and regulation of hepatocyte death during HBV-ACLF progression are still undefined. Evaluating the mode of cell death and its inducers will provide new insights for developing therapeutic strategies targeting cell death. In this study, we aimed to elucidate whether and how immune landscapes trigger hepatocyte death and lead to the progression of HBV-related ACLF. APPROACH AND RESULTS: We identified that pyroptosis represented the main cell death pattern in the liver of patients with HBV-related ACLF. Deficiency of MHC-I in HBV-reactivated hepatocytes activated cytotoxic NK cells, which in turn operated in a perforin/granzyme-dependent manner to trigger GSDMD/caspase-8-dependent pyroptosis of hepatocytes. Neutrophils selectively accumulated in the pyroptotic liver, and HMGB1 derived from the pyroptotic liver constituted an important factor triggering the generation of pathogenic extracellular traps in neutrophils (NETs). Clinically, elevated plasma levels of myeloperoxidase-DNA complexes were a promising prognostic biomarker for HBV-related ACLF. More importantly, targeting GSDMD pyroptosis-HMGB1 release in the liver abrogates NETs that intercept the development of HBV-related ACLF. CONCLUSIONS: Studying the mechanisms that selectively modulate GSDMD-dependent pyroptosis, as well as its immune landscapes, will provide a novel strategy for restoring the liver function of patients with HBV-related ACLF.

5.
Mol Ther ; 32(4): 1110-1124, 2024 Apr 03.
Article in English | MEDLINE | ID: mdl-38341612

ABSTRACT

Whether and how tumor intrinsic signature determines macrophage-elicited metastasis remain elusive. Here, we show, in detailed studies of data regarding 7,477 patients of 20 types of human cancers, that only 13.8% ± 2.6%/27.9% ± 3.03% of patients with high macrophage infiltration index exhibit early recurrence/vascular invasion. In parallel, although macrophages enhance the motility of various hepatoma cells, their enhancement intensity is significantly heterogeneous. We identify that the expression of malignant Dicer, a ribonuclease that cleaves miRNA precursors into mature miRNAs, determines macrophage-elicited metastasis. Mechanistically, the downregulation of Dicer in cancer cells leads to defects in miRNome targeting NF-κB signaling, which in turn enhances the ability of cancer cells to respond to macrophage-related inflammatory signals and ultimately promotes metastasis. Importantly, transporting miR-26b-5p, the most potential miRNA targeting NF-κB signaling in hepatocellular carcinoma, can effectively reverse macrophage-elicited metastasis of hepatoma in vivo. Our results provide insights into the crosstalk between Dicer-elicited miRNome and cancer immune microenvironments and suggest that strategies to remodel malignant cell miRNome may overcome pro-tumorigenic activities of inflammatory cells.


Subject(s)
Carcinoma, Hepatocellular , MicroRNAs , Humans , NF-kappa B/genetics , NF-kappa B/metabolism , Carcinoma, Hepatocellular/pathology , Signal Transduction/physiology , MicroRNAs/genetics , MicroRNAs/metabolism , Macrophages/metabolism , Cell Line, Tumor , Tumor Microenvironment/genetics
6.
Ann Rheum Dis ; 83(5): 608-623, 2024 Apr 11.
Article in English | MEDLINE | ID: mdl-38290829

ABSTRACT

OBJECTIVES: The current work aimed to provide a comprehensive single-cell landscape of lupus nephritis (LN) kidneys, including immune and non-immune cells, identify disease-associated cell populations and unravel their participation within the kidney microenvironment. METHODS: Single-cell RNA and T cell receptor sequencing were performed on renal biopsy tissues from 40 patients with LN and 6 healthy donors as controls. Matched peripheral blood samples from seven LN patients were also sequenced. Multiplex immunohistochemical analysis was performed on an independent cohort of 60 patients and validated using flow cytometric characterisation of human kidney tissues and in vitro assays. RESULTS: We uncovered a notable enrichment of CD163+ dendritic cells (DC3s) in LN kidneys, which exhibited a positive correlation with the severity of LN. In contrast to their counterparts in blood, DC3s in LN kidney displayed activated and highly proinflammatory phenotype. DC3s showed strong interactions with CD4+ T cells, contributing to intrarenal T cell clonal expansion, activation of CD4+ effector T cell and polarisation towards Th1/Th17. Injured proximal tubular epithelial cells (iPTECs) may orchestrate DC3 activation, adhesion and recruitment within the LN kidneys. In cultures, blood DC3s treated with iPTECs acquired distinct capabilities to polarise Th1/Th17 cells. Remarkably, the enumeration of kidney DC3s might be a potential biomarker for induction treatment response in LN patients. CONCLUSION: The intricate interplay involving DC3s, T cells and tubular epithelial cells within kidneys may substantially contribute to LN pathogenesis. The enumeration of renal DC3 holds potential as a valuable stratification feature for guiding LN patient treatment decisions in clinical practice.


Subject(s)
Lupus Erythematosus, Systemic , Lupus Nephritis , Humans , Biomarkers/metabolism , Dendritic Cells/metabolism , Kidney/pathology , Lupus Erythematosus, Systemic/pathology , Lupus Nephritis/pathology , Th1 Cells , Antigens, Differentiation, Myelomonocytic , Antigens, CD
7.
Mol Ther ; 31(1): 105-118, 2023 01 04.
Article in English | MEDLINE | ID: mdl-36183166

ABSTRACT

Epigenetic reprogramming is a promising therapeutic strategy for aggressive cancers, but its limitations in vivo remain unclear. Here, we showed, in detailed studies of data regarding 410 patients with human hepatocellular carcinoma (HCC), that increased histone methyltransferase DOT1L triggered epithelial-mesenchymal transition-mediated metastasis and served as a therapeutic target for human HCC. Unexpectedly, although targeting DOT1L in vitro abrogated the invasive potential of hepatoma cells, abrogation of DOT1L signals hardly affected the metastasis of hepatoma in vivo. Macrophages, which constitute the major cellular component of the stroma, abrogated the anti-metastatic effect of DOT1L targeting. Mechanistically, NF-κB signal elicited by macrophage inflammatory response operated via a non-epigenetic machinery to eliminate the therapeutic efficacy of DOT1L targeting. Importantly, therapeutic strategy combining DOT1L-targeted therapy with macrophage depletion or NF-κB inhibition in vivo effectively and successfully elicited cancer regression. Moreover, we found that the densities of macrophages in HCC determined malignant cell DOT1L-associated clinical outcome of the patients. Our results provide insight into the crosstalk between epigenetic reprogramming and cancer microenvironments and suggest that strategies to influence the functional activities of inflammatory cells may benefit epigenetic reprogramming therapy.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , NF-kappa B , Cell Line , Macrophages/pathology , Tumor Microenvironment , Histone-Lysine N-Methyltransferase/genetics
8.
Gut ; 72(6): 1196-1210, 2023 06.
Article in English | MEDLINE | ID: mdl-36596711

ABSTRACT

OBJECTIVE: Revealing the single-cell immune ecosystems in true versus de novo hepatocellular carcinoma (HCC) recurrences could help the optimal development of immunotherapies. DESIGN: We performed 5'and VDJ single-cell RNA-sequencing on 34 samples from 20 recurrent HCC patients. Bulk RNA-sequencing, flow cytometry, multiplexed immunofluorescence, and in vitro functional analyses were performed on samples from two validation cohorts. RESULTS: Analyses of mutational profiles and evolutionary trajectories in paired primary and recurrent HCC samples using whole-exome sequencing identified de novo versus true recurrences, some of which occurred before clinical diagnosis. The tumour immune microenvironment (TIME) of truly recurrent HCCs was characterised by an increased abundance in KLRB1+CD8+ T cells with memory phenotype and low cytotoxicity. In contrast, we found an enrichment in cytotoxic and exhausted CD8+ T cells in the TIME of de novo recurrent HCCs. Transcriptomic and interaction analyses showed elevated GDF15 expression on HCC cells in proximity to dendritic cells, which may have dampened antigen presentation and inhibited antitumour immunity in truly recurrent lesions. In contrast, myeloid cells' cross talk with T cells-mediated T cell exhaustion and immunosuppression in the TIME of de novo recurrent HCCs. Consistent with these findings, a phase 2 trial of neoadjuvant anti-PD-1 immunotherapy showed more responses in de novo recurrent HCC patients. CONCLUSION: True and de novo HCC recurrences occur early, have distinct TIME and may require different immunotherapy strategies. Our study provides a source for genomic diagnosis and immune profiling for guiding immunotherapy based on the type of HCC recurrence and the specific TIME.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/metabolism , Hepatitis B virus/genetics , CD8-Positive T-Lymphocytes , Ecosystem , RNA/metabolism , Tumor Microenvironment
9.
Cell Mol Life Sci ; 78(3): 867-887, 2021 Feb.
Article in English | MEDLINE | ID: mdl-32940722

ABSTRACT

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.


Subject(s)
B7-H1 Antigen/metabolism , Neoplasms/pathology , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , B7-H1 Antigen/immunology , Humans , Immune Checkpoint Inhibitors/therapeutic use , Neoplasms/drug therapy , Neoplasms/immunology , Programmed Cell Death 1 Receptor/immunology , Programmed Cell Death 1 Receptor/metabolism , Protein Processing, Post-Translational , Signal Transduction , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Tumor Microenvironment
10.
Pharmacol Res ; 174: 105966, 2021 12.
Article in English | MEDLINE | ID: mdl-34728366

ABSTRACT

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.


Subject(s)
Gastrointestinal Microbiome , Neoplasms/microbiology , Neoplasms/therapy , Animals , Humans , Neoplasms/immunology , Tumor Microenvironment/immunology
11.
Gastroenterology ; 156(6): 1890-1904.e16, 2019 05.
Article in English | MEDLINE | ID: mdl-30711627

ABSTRACT

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.


Subject(s)
Carcinoma, Hepatocellular/genetics , Epigenesis, Genetic , Immunoglobulin G/metabolism , Liver Neoplasms/genetics , Macrophages/metabolism , Plasma Cells/metabolism , Adult , Aged , Animals , Antimetabolites, Antineoplastic/pharmacology , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Differentiation , Cell Line, Tumor , Chemokine CCL20/metabolism , Chemokine CXCL10/metabolism , DNA (Cytosine-5-)-Methyltransferase 1/metabolism , Decitabine/pharmacology , Disease Progression , Enhancer of Zeste Homolog 2 Protein/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Humans , Indoles/pharmacology , Interleukin-10/metabolism , Interleukin-6/metabolism , Liver/pathology , Liver Neoplasms/immunology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Lymphocyte Count , Male , Mice , Middle Aged , Neoplasm Transplantation , Phenotype , Plasma Cells/immunology , Pyridones/pharmacology , Receptors, CXCR3/metabolism , Receptors, Fc/metabolism , Signal Transduction , Transcriptome
12.
J Hepatol ; 71(2): 333-343, 2019 08.
Article in English | MEDLINE | ID: mdl-31071366

ABSTRACT

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.


Subject(s)
B7-H1 Antigen/metabolism , Carcinoma, Hepatocellular/immunology , Glycolysis , Immune Privilege , Liver Neoplasms/immunology , Monocytes/metabolism , Phosphofructokinase-2/metabolism , Adult , Aged , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , CD8-Positive T-Lymphocytes/immunology , Carcinoma, Hepatocellular/blood , Carcinoma, Hepatocellular/pathology , Disease Progression , Female , Follow-Up Studies , Hep G2 Cells , Humans , Liver Neoplasms/blood , Liver Neoplasms/pathology , Macrophages/metabolism , Male , Middle Aged , Monocytes/immunology , Tumor Microenvironment/immunology , Young Adult
13.
Hepatology ; 62(6): 1779-90, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26235097

ABSTRACT

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.


Subject(s)
B-Lymphocytes/physiology , Carcinoma, Hepatocellular/immunology , Inflammation/immunology , Interleukin-17/physiology , Liver Neoplasms/immunology , Macrophages/physiology , Receptors, CXCR3/physiology , Animals , Female , Humans , Mice , Mice, Inbred C57BL
14.
J Hepatol ; 62(1): 131-9, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25152203

ABSTRACT

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.


Subject(s)
Autophagy , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Neutrophils/ultrastructure , Adult , Aged , Apoptosis , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Cell Survival , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunoblotting , Liver Neoplasms/metabolism , Male , Microscopy, Electron, Transmission , Middle Aged , Signal Transduction
15.
Hepatology ; 57(3): 1107-16, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23225218

ABSTRACT

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.


Subject(s)
Antigens, CD/immunology , Carcinoma, Hepatocellular/immunology , Killer Cells, Natural/immunology , Liver Neoplasms/immunology , Monocytes/immunology , Receptors, Immunologic/immunology , Antigens, CD/metabolism , Apoptosis/immunology , CD48 Antigen , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Cell Communication/immunology , Cell Survival/immunology , Female , Humans , Interferon-gamma/metabolism , Killer Cells, Natural/metabolism , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Macrophages/immunology , Macrophages/metabolism , Male , Middle Aged , Monocytes/metabolism , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Receptors, Immunologic/metabolism , Signaling Lymphocytic Activation Molecule Family , Tumor Microenvironment/immunology , Tumor Necrosis Factor-alpha/metabolism
16.
J Immunol ; 188(3): 1117-24, 2012 Feb 01.
Article in English | MEDLINE | ID: mdl-22184722

ABSTRACT

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.


Subject(s)
Antigens, CD , Antigens, Differentiation, T-Lymphocyte , Carcinoma, Hepatocellular/immunology , Immune Tolerance , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Lectins, C-Type , Macrophages/metabolism , T-Lymphocytes/immunology , Humans , Lymphocyte Activation , Tryptophan
17.
Cancer Res ; 84(6): 841-854, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38231484

ABSTRACT

Triggering ferroptosis, an iron-dependent form of cell death, has recently emerged as an approach for treating cancer. A better understanding of the role and regulation of ferroptosis is needed to realize the potential of this therapeutic strategy. Here, we observed extensive activation of ferroptosis in hepatoma cells and human hepatocellular carcinoma (HCC) cases. Patients with low to moderate activation of ferroptosis in tumors had the highest risk of recurrence compared to patients with no or high ferroptosis. Upon encountering ferroptotic liver cancer cells, aggregated macrophages efficiently secreted proinflammatory IL1ß to trigger neutrophil-mediated sinusoidal vascular remodeling, thereby creating favorable conditions for aggressive tumor growth and lung metastasis. Mechanistically, hyaluronan fragments released by cancer cells acted via an NF-κB-dependent pathway to upregulate IL1ß precursors and the NLRP3 inflammasome in macrophages, and oxidized phospholipids secreted by ferroptotic cells activated the NLRP3 inflammasome to release functional IL1ß. Depleting either macrophages or neutrophils or neutralizing IL1ß in vivo effectively abrogated ferroptosis-mediated liver cancer growth and lung metastasis. More importantly, the ferroptosis-elicited inflammatory cellular network served as a negative feedback mechanism that led to therapeutic resistance to sorafenib in HCC. Targeting the ferroptosis-induced inflammatory axis significantly improved the therapeutic efficacy of sorafenib in vivo. Together, this study identified a role for ferroptosis in promoting HCC by triggering a macrophage/IL1ß/neutrophil/vasculature axis. SIGNIFICANCE: Ferroptosis induces a favorable tumor microenvironment and supports liver cancer progression by stimulating an inflammatory cellular network that can be targeted to suppress metastasis and improve the efficacy of sorafenib.


Subject(s)
Carcinoma, Hepatocellular , Ferroptosis , Liver Neoplasms , Lung Neoplasms , Humans , Carcinoma, Hepatocellular/drug therapy , Sorafenib/pharmacology , NLR Family, Pyrin Domain-Containing 3 Protein , Inflammasomes , Liver Neoplasms/drug therapy , Inflammation/drug therapy , Lung Neoplasms/drug therapy , Cell Line, Tumor , Tumor Microenvironment
18.
Cancer Res ; 83(21): 3544-3561, 2023 11 01.
Article in English | MEDLINE | ID: mdl-37352379

ABSTRACT

The tumor microenvironment is distinctive in primary and secondary liver cancer. B cells represent an important component of immune infiltrates. Here, we demonstrated that B cells are an important regulator in hepatocellular carcinoma (HCC) and colorectal cancer liver metastasis (CRLM) microenvironments. B cells displayed distinct developmental trajectories in HCC and CRLM. Single-cell analysis revealed that IgG+ plasma cells preferentially accumulated in HCC, whereas IgA+ plasma cells were preferentially enriched in CRLM. Mechanistically, IgG+ plasma cells in HCC were recruited by tumor-associated macrophages via the CXCR3-CXCL10 axis, whereas IgA+ plasma cells in CRLM were recruited by metastatic tumor cells via CCR10-CCL28 signaling. Functionally, IgG+ plasma cells preferentially promoted protumorigenic macrophages formation in HCC, and IgA+ plasma cells preferentially induced granulocytic myeloid-derived suppressor cells activation in CRLM. Clinically, increased infiltration of IgG+ plasma cells and macrophages in HCC was correlated to worse survival, whereas increased intratumoral IgA+ plasma cells and neutrophils in CRLM indicated poor prognosis. Taken together, this study demonstrated plasma and myeloid cell-mediated immunosuppression in HCC and CRLM, suggesting that selectively modulating primary or secondary tumor-related immunosuppressive regulatory networks might reprogram the microenvironment and provide an immunotherapeutic strategy for treating liver cancer. SIGNIFICANCE: The immunomodulatory patterns of tumor-infiltrating B cells are distinct in primary and secondary liver cancer, with plasma cells mediating important physiologic processes that drive cancer progression.


Subject(s)
Carcinoma, Hepatocellular , Colorectal Neoplasms , Liver Neoplasms , Humans , Liver Neoplasms/pathology , Carcinoma, Hepatocellular/pathology , Signal Transduction , Colorectal Neoplasms/pathology , Immunoglobulin G , Immunoglobulin A , Tumor Microenvironment
19.
Nat Med ; 29(6): 1424-1436, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37280275

ABSTRACT

Gemcitabine plus cisplatin (GP) chemotherapy is the standard of care for nasopharyngeal carcinoma (NPC). However, the mechanisms underpinning its clinical activity are unclear. Here, using single-cell RNA sequencing and T cell and B cell receptor sequencing of matched, treatment-naive and post-GP chemotherapy NPC samples (n = 15 pairs), we show that GP chemotherapy activated an innate-like B cell (ILB)-dominant antitumor immune response. DNA fragments induced by chemotherapy activated the STING type-I-interferon-dependent pathway to increase major histocompatibility complex class I expression in cancer cells, and simultaneously induced ILB via Toll-like receptor 9 signaling. ILB further expanded follicular helper and helper type 1 T cells via the ICOSL-ICOS axis and subsequently enhanced cytotoxic T cells in tertiary lymphoid organ-like structures after chemotherapy that were deficient for germinal centers. ILB frequency was positively associated with overall and disease-free survival in a phase 3 trial of patients with NPC receiving GP chemotherapy ( NCT01872962 , n = 139). It also served as a predictor for favorable outcomes in patients with NPC treated with GP and immunotherapy combined treatment (n = 380). Collectively, our study provides a high-resolution map of the tumor immune microenvironment after GP chemotherapy and uncovers a role for B cell-centered antitumor immunity. We also identify and validate ILB as a potential biomarker for GP-based treatment in NPC, which could improve patient management.


Subject(s)
Cisplatin , Nasopharyngeal Neoplasms , Humans , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/pathology , Cisplatin/therapeutic use , Gemcitabine , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/etiology , Nasopharyngeal Neoplasms/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Deoxycytidine/therapeutic use , Tumor Microenvironment
20.
Eur J Immunol ; 41(8): 2314-22, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21674477

ABSTRACT

Substantial evidence indicates that inflammation is a critical component of tumor progression. The proinflammatory IL-17-producing cells have recently been detected in tumors, but the effect of IL-17 on antigen-presenting cells in tumors is presently unknown. We recently found that B7-H1(+) macrophages (Mφs) were enriched predominantly in the peritumoral stroma of hepatocellular carcinomas (HCCs). Here, we found a positive correlation between IL-17-producing cells and B7-H1-expressing Mφs in the same area. The B7-H1(+) monocytes/Mφs from HCC tissues expressed significantly more HLA-DR, CD80, and CD86 than B7-H1(-) cells. Accordingly, IL-17 could activate monocytes to express B7-H1 in a dose-dependent manner. Although culture supernatants derived from hepatoma cells also induced B7-H1 expression on monocytes, IL-17 additionally increased hepatoma-mediated B7-H1 expression. Autocrine inflammatory cytokines released from IL-17-activated monocytes stimulated B7-H1 expression. Moreover, these IL-17-exposed monocytes effectively suppressed cytotoxic T-cell immunity in vitro; the effect could be reversed by blocking B7-H1 on those monocytes. Consistent with this, cytotoxic T cells from HCC tissues expressed significant B7-H1 receptor programmed death 1 (PD-1) and exhibited an exhausted phenotype. These data reveal a fine-tuned collaborative action between different stromal cells to counteract T-cell responses in tumors. Such IL-17-mediated immune tolerance should be considered for the rational design of effective immune-based anti-cancer therapies.


Subject(s)
Antigens, CD/immunology , Carcinoma, Hepatocellular/immunology , Interleukin-17/immunology , Liver Neoplasms/immunology , Monocytes/immunology , T-Lymphocytes, Cytotoxic/immunology , Adult , Aged , Antigens, CD/metabolism , Apoptosis Regulatory Proteins/immunology , Apoptosis Regulatory Proteins/metabolism , B7-H1 Antigen , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Count , Cells, Cultured , Coculture Techniques , Cytotoxicity, Immunologic/drug effects , Cytotoxicity, Immunologic/immunology , Female , Flow Cytometry , Hep G2 Cells , Humans , Immunohistochemistry , Interleukin-17/metabolism , Interleukin-17/pharmacology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Macrophages/immunology , Macrophages/metabolism , Male , Middle Aged , Monocytes/drug effects , Monocytes/metabolism , Programmed Cell Death 1 Receptor , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism , Young Adult
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