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1.
Cell Commun Signal ; 21(1): 117, 2023 05 19.
Article in English | MEDLINE | ID: mdl-37208766

ABSTRACT

Cancer-associated anemia promotes tumor progression, leads to poor quality of life in patients with cancer, and even obstructs the efficacy of immune checkpoint inhibitors therapy. However, the precise mechanism for cancer-associated anemia remains unknown and the feasible strategy to target cancer-associated anemia synergizing immunotherapy needs to be clarified. Here, we review the possible mechanisms of cancer-induced anemia regarding decreased erythropoiesis and increased erythrocyte destruction, and cancer treatment-induced anemia. Moreover, we summarize the current paradigm for cancer-associated anemia treatment. Finally, we propose some prospective paradigms to slow down cancer-associated anemia and synergistic the efficacy of immunotherapy. Video Abstract.


Subject(s)
Anemia , Neoplasms , Humans , Prospective Studies , Quality of Life , Anemia/complications , Anemia/therapy , Neoplasms/complications , Neoplasms/therapy , Immunotherapy
2.
Cell Mol Life Sci ; 79(3): 191, 2022 Mar 16.
Article in English | MEDLINE | ID: mdl-35292881

ABSTRACT

Immune checkpoint blockade (ICB) therapies have achieved remarkable clinical responses in patients with many different types of cancer; however, most patients who receive ICB monotherapy fail to achieve long-term responses, and some tumors become immunotherapy-resistant and even hyperprogressive. Type I interferons (IFNs) have been demonstrated to inhibit tumor growth directly and indirectly by acting upon tumor and immune cells, respectively. Furthermore, accumulating evidence indicates that endo- and exogenously enhancing type I IFNs have a synergistic effect on anti-tumor immunity. Therefore, clinical trials studying new treatment strategies that combine type I IFN inducers with ICB are currently in progress. Here, we review the cellular sources of type I IFNs and their roles in the immune regulation of the tumor microenvironment. In addition, we highlight immunotherapies based on type I IFNs and combination therapy between type I IFN inducers and ICBs.


Subject(s)
Immunotherapy/methods , Interferon Type I/immunology , Neoplasms/immunology , Neoplasms/therapy , Animals , Cancer-Associated Fibroblasts/immunology , Combined Modality Therapy , Dendritic Cells/immunology , Endothelial Cells/immunology , Humans , Immune Checkpoint Inhibitors/therapeutic use , Interferon Type I/biosynthesis , Killer Cells, Natural/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Macrophages/immunology , Mice , Models, Immunological , Myeloid-Derived Suppressor Cells/immunology , Neutrophils/immunology , Oncolytic Virotherapy , Signal Transduction/immunology , T-Lymphocytes, Regulatory/immunology , Toll-Like Receptors/agonists , Tumor Microenvironment/immunology
3.
Cells ; 10(4)2021 04 14.
Article in English | MEDLINE | ID: mdl-33919979

ABSTRACT

Macrophages are widely distributed in tissues and function in homeostasis. During cancer development, tumor-associated macrophages (TAMs) dominatingly support disease progression and resistance to therapy by promoting tumor proliferation, angiogenesis, metastasis, and immunosuppression, thereby making TAMs a target for tumor immunotherapy. Here, we started with evidence that TAMs are highly plastic and heterogeneous in phenotype and function in response to microenvironmental cues. We pointed out that efforts to tear off the heterogeneous "camouflage" in TAMs conduce to target de facto protumoral TAMs efficiently. In particular, several fate-mapping models suggest that most tissue-resident macrophages (TRMs) are generated from embryonic progenitors, and new paradigms uncover the ontogeny of TAMs. First, TAMs from embryonic modeling of TRMs and circulating monocytes have distinct transcriptional profiling and function, suggesting that the ontogeny of TAMs is responsible for the functional heterogeneity of TAMs, in addition to microenvironmental cues. Second, metabolic remodeling helps determine the mechanism of phenotypic and functional characteristics in TAMs, including metabolic bias from macrophages' ontogeny in macrophages' functional plasticity under physiological and pathological conditions. Both models aim at dissecting the ontogeny-related metabolic regulation in the phenotypic and functional heterogeneity in TAMs. We argue that gleaning from the single-cell transcriptomics on subclonal TAMs' origins may help understand the classification of TAMs' population in subclonal evolution and their distinct roles in tumor development. We envision that TAM-subclone-specific metabolic reprogramming may round-up with future cancer therapies.


Subject(s)
Embryo, Mammalian/pathology , Neoplasms/pathology , Neoplasms/prevention & control , Tumor-Associated Macrophages/pathology , Glucose/metabolism , Humans , Lipid Metabolism , Neoplasms/metabolism , Single-Cell Analysis
4.
Theranostics ; 11(3): 1016-1030, 2021.
Article in English | MEDLINE | ID: mdl-33391518

ABSTRACT

Macrophages phagocytize pathogens to initiate innate immunity and products from the tumor microenvironment (TME) to mediate tumor immunity. The loss of tumor-associated macrophage (TAM)-mediated immune responses results in immune suppression. To reverse this immune disorder, the regulatory mechanism of TAMs in the TME needs to be clarified. Immune molecules (cytokines and chemokines) from TAMs and the TME have been widely accepted as mutual mediators of signal transduction in the past few decades. Recently, researchers have tried to seek the intrinsic mechanism of TAM phenotypic and functional changes through metabolic connections. Numerous metabolites derived from the TME have been identified that induce the cell-cell crosstalk with TAMs. The bulk tumor cells, immune cells, and stromal cells produce metabolites in the TME that are involved in the metabolic regulation of TAMs. Meanwhile, some products from TAMs regulate the biological functions of the tumor as well. Here, we review the recent reports demonstrating the metabolic regulation between TME and TAMs.


Subject(s)
Neoplasms/metabolism , Tumor Microenvironment/physiology , Tumor-Associated Macrophages/metabolism , Tumor-Associated Macrophages/physiology , Animals , Humans , Immunity, Innate/physiology , Signal Transduction/physiology
7.
Cell Mol Life Sci ; 77(14): 2723-2738, 2020 Jul.
Article in English | MEDLINE | ID: mdl-31974657

ABSTRACT

Extramedullary hematopoiesis (EMH) is the expansion and differentiation of hematopoietic stem and progenitor cells outside of the bone marrow. In postnatal life, as a compensatory mechanism for ineffective hematopoiesis of the bone marrow, pathological EMH is triggered by hematopoietic disorders, insufficient hematopoietic compensation, and other pathological stress conditions, such as infection, advanced tumors, anemia, and metabolic stress. Pathological EMH has been reported in many organs, and the sites of pathological EMH may be related to reactivation of the embryonic hematopoietic structure in these organs. As a double-edged sword (blood and immune cell supplementation as well as clinical complications), pathological EMH has been widely studied in recent years. In particular, pathological EMH induced by late-stage tumors contributes to tumor immunosuppression. Thus, a deeper understanding of the mechanism of pathological EMH may be conducive to the development of therapies against the pathological processes that induce EMH. This article reviews the recent progress of research on the cellular and molecular mechanisms of pathological EMH in specific diseases.


Subject(s)
Embryonic Stem Cells , Hematopoiesis, Extramedullary/genetics , Hematopoietic Stem Cells , Neoplasms/genetics , Humans , Immunosuppression Therapy , Neoplasms/pathology , Stress, Physiological/genetics
8.
Biochem Biophys Res Commun ; 517(2): 201-209, 2019 09 17.
Article in English | MEDLINE | ID: mdl-31331645

ABSTRACT

Lung cancer is the most commonly diagnosed cancer and accounts for most cancer-related mortalities worldwide. The high expression of programmed death ligand 1 (PD-L1) is an important factor that promotes immune escape of lung cancer, thus aggravates chemotherapy resistance and poor prognosis. Therefore, understanding the regulatory mechanism of PD-L1 in lung cancer is critical for tumor immunotherapy. Enhancer of Zeste homolog2 (EZH2), an epigenetic regulatory molecule with histone methyltransferase activity, promotes the formation of an immunosuppressive microenvironment. This study aimed to investigate the role of EZH2 in PD-L1 expression and in the progression of lung tumors. We found that EZH2 was upregulated in lung cancer tissues and positively correlated with PD-L1 levels and poor prognosis. Further, shRNA-expressing lentivirus mediated EZH2 knockdown suppressed both the mRNA and protein expression level of PD-L1, thus delaying lung cancer progression in vivo by enhancing anti-tumor immune responses. Moreover, the regulatory effect of EZH2 on PD-L1 depended on HIF-1α. The present results indicate that EZH2 regulates the immunosuppressive molecule PD-L1 expression via HIF-1α in non-small cell lung cancer cells.


Subject(s)
B7-H1 Antigen/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism , Gene Expression Regulation, Neoplastic , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Lung Neoplasms/genetics , Animals , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Female , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice, Inbred C57BL
9.
Cell Biol Int ; 43(2): 117-124, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30203888

ABSTRACT

Colorectal cancer (CRC) is the third most common type of cancer, and its incidence and mortality are markedly increasing worldwide. Oncogenic mutations of KRAS occur in up to 40% of CRC cases and pose a great challenge in the treatment of the disease. Quercetin is a dietary flavonoid that exerts anti-oxidant, anti-inflammatory, and anti-cancer properties. The current study investigated the anti-proliferative effect of quercetin on CRC cells harboring mutant or wild-type KRAS. The effect of quercetin on cell viability was investigated by MTT and colony formation assays, and apoptosis was detected using flow cytometry by labeling cells with Annexin V-FITC. The expression of the relevant proteins was examined by Western blotting. The data revealed that KRAS-mutant cells were more sensitive to quercetin-induced apoptosis than wild-type cells. Caspase activation was involved in quercetin-induced apoptosis. In addition, quercetin selectively activated the c-Jun N-terminal kinase (JNK) pathway in KRAS-mutant cells, while inhibition of phospho-JNK by SP600125 blocked quercetin-induced apoptosis. The results of the present study suggest that treatment with quercetin, a common flavonoid in plants, is potentially a useful strategy for the treatment of CRCs carrying KRAS mutations.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , JNK Mitogen-Activated Protein Kinases/metabolism , MAP Kinase Signaling System/drug effects , Proto-Oncogene Proteins p21(ras)/genetics , Quercetin/pharmacology , Anthracenes/pharmacology , Caspases/metabolism , Cell Line, Tumor , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Humans , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Mutation , Proto-Oncogene Proteins c-akt/metabolism
10.
Cancer Immunol Res ; 6(9): 1046-1056, 2018 09.
Article in English | MEDLINE | ID: mdl-30002156

ABSTRACT

Despite the frequency of lung metastasis and its associated mortality, the mechanisms behind metastatic tumor cell survival and colonization in the lungs remain elusive. Here, we show that tumor cell-released microparticles (T-MPs) from the primary tumor site play a critical role in the metastatic process. The T-MPs remodeled the lung parenchyma via a macrophage-dependent pathway to create an altered inflammatory and mechanical response to tumor cell invasion. Mechanistically, we show that circulating T-MPs readily enter the lung parenchyma where they are taken up by local macrophages and induce CCL2 production. CCL2 recruits CD11b+Ly6Chigh inflammatory monocytes to the lungs where they mature into F4/80+CD11b+Ly6C- macrophages that not only produce IL6 but also trigger fibrin deposition. IL6 and the deposited fibrin facilitate the survival and growth of tumor-repopulating cells in the lungs by providing chemical and mechanical signals, respectively, thus setting the stage for lung metastasis. These data illustrate that T-MPs reprogram the lung microenvironment promoting metastasis. Cancer Immunol Res; 6(9); 1046-56. ©2018 AACR.


Subject(s)
Cell-Derived Microparticles/immunology , Inflammation , Lung Neoplasms/pathology , Macrophages/immunology , Neoplasm Metastasis/immunology , Animals , Cell-Derived Microparticles/pathology , Female , Lung/cytology , Lung/immunology , Lung Neoplasms/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Tumor Microenvironment/immunology
11.
Nat Commun ; 9(1): 1808, 2018 05 01.
Article in English | MEDLINE | ID: mdl-29717137

ABSTRACT

In the originally published version of this Article, images in Fig. 5n were inadvertently replaced with duplicates of images in Fig. 5o during the production process. This has now been corrected in both the PDF and HTML versions of the Article.

12.
Cancer Res ; 78(14): 3926-3937, 2018 07 15.
Article in English | MEDLINE | ID: mdl-29764867

ABSTRACT

Dormancy is recognized as a critical biological event for tumorigenic cells surviving in an extremely harsh environment. Understanding the molecular process of dormancy can unlock novel approaches to tackle cancers. We recently reported that stem-like tumor-repopulating cells (TRC) sense mechanical signals and rapidly proliferate in a 90 Pa soft fibrin matrix. Here, we show that a stiff mechanical environment induces TRC dormancy via an epigenetic program initiated by translocation of Cdc42, a cytosolic regulator of mechanotransduction, into the nucleus, where it promotes transcription of hydroxymethylating enzyme Tet2. Tet2 epigenetically activated cell-cycle-inhibiting genes p21 and p27 to induce dormancy, but also caused downregulation of integrin ß3 to maintain dormancy. This stiffness-mediated dormancy was recapitulated in mouse models for both murine and primary human melanoma TRCs. These data identify an epigenetic program directed by mechanics, which drives highly tumorigenic TRCs to enter dormancy in a stiff mechanical environment.Significance: A mechanics-directed epigenetic program enables tumor-repopulating cells to enter dormancy in a stiff mechanical environment. Cancer Res; 78(14); 3926-37. ©2018 AACR.


Subject(s)
DNA-Binding Proteins/metabolism , Epigenesis, Genetic/physiology , Fibrin/metabolism , Proto-Oncogene Proteins/metabolism , cdc42 GTP-Binding Protein/metabolism , A549 Cells , Animals , Cell Line , Cell Line, Tumor , Cell Proliferation/physiology , Dioxygenases , Down-Regulation/physiology , Epigenomics/methods , Female , Hep G2 Cells , Humans , Mechanotransduction, Cellular/physiology , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, SCID
13.
Nat Commun ; 9(1): 873, 2018 02 28.
Article in English | MEDLINE | ID: mdl-29491374

ABSTRACT

Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment and improve innate and adaptive antitumor immunity. Here we show that chloroquine (CQ), a proven anti-malarial drug, can function as an antitumor immune modulator that switches TAMs from M2 to tumor-killing M1 phenotype. Mechanistically, CQ increases macrophage lysosomal pH, causing Ca2+ release via the lysosomal Ca2+ channel mucolipin-1 (Mcoln1), which induces the activation of p38 and NF-κB, thus polarizing TAMs to M1 phenotype. In parallel, the released Ca2+ activates transcription factor EB (TFEB), which reprograms the metabolism of TAMs from oxidative phosphorylation to glycolysis. As a result, CQ-reset macrophages ameliorate tumor immune microenvironment by decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and Treg cells, thus enhancing antitumor T-cell immunity. These data illuminate a previously unrecognized antitumor mechanism of CQ, suggesting a potential new macrophage-based tumor immunotherapeutic modality.


Subject(s)
Antineoplastic Agents/pharmacology , Chloroquine/pharmacology , Immunotherapy/methods , Macrophages/cytology , Macrophages/immunology , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Calcium/metabolism , Calcium Channels/metabolism , Cell Line, Tumor , Female , Glycolysis/physiology , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Nude , Mice, Transgenic , NF-kappa B/metabolism , RAW 264.7 Cells , Transient Receptor Potential Channels/metabolism , Tumor Microenvironment/immunology , p38 Mitogen-Activated Protein Kinases/metabolism
14.
Cancer Cell ; 33(3): 480-494.e7, 2018 03 12.
Article in English | MEDLINE | ID: mdl-29533786

ABSTRACT

Despite the clinical successes fostered by immune checkpoint inhibitors, mechanisms underlying PD-1 upregulation in tumor-infiltrating T cells remain an enigma. Here, we show that tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8+ T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway. Interferon-γ produced by CD8+ T cells stimulates release of high levels of Kyn produced by TRCs, which is transferred into adjacent CD8+ T cells via the transporters SLC7A8 and PAT4. Kyn induces and activates AhR and thereby upregulates PD-1 expression. This Kyn-AhR pathway is confirmed in both tumor-bearing mice and cancer patients and its blockade enhances antitumor adoptive T cell therapy efficacy. Thus, we uncovered a mechanism of PD-1 upregulation with potential tumor immunotherapeutic applications.


Subject(s)
CD8-Positive T-Lymphocytes/drug effects , Kynurenine/pharmacology , Programmed Cell Death 1 Receptor/drug effects , Receptors, Aryl Hydrocarbon/drug effects , Animals , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Humans , Interferon-gamma/immunology , Mice , Programmed Cell Death 1 Receptor/immunology , Programmed Cell Death 1 Receptor/metabolism , Signal Transduction/drug effects , Signal Transduction/immunology
15.
J Clin Invest ; 128(3): 1057-1073, 2018 03 01.
Article in English | MEDLINE | ID: mdl-29431732

ABSTRACT

Dynamic interaction with the immune system profoundly regulates tumor cell dormancy. However, it is unclear how immunological cues trigger cancer cell-intrinsic signaling pathways for entering into dormancy. Here, we show that IFN-ß treatment induced tumor-repopulating cells (TRC) to enter dormancy through an indolamine 2,3-dioxygenase/kynurenine/aryl hydrocarbon receptor/p27-dependent (IDO/Kyn/AhR/p27-dependent) pathway. Strategies to block this metabolic circuitry did not relieve dormancy, but led to apoptosis of dormant TRCs in murine and human melanoma models. Specifically, blocking AhR redirected IFN-ß signaling to STAT3 phosphorylation through both tyrosine and serine sites, which subsequently facilitated STAT3 nuclear translocation and subsequent binding to the p53 promoter in the nucleus. Upregulation of p53 in turn disrupted the pentose phosphate pathway, leading to excessive ROS production and dormant TRC death. Additionally, in melanoma patients, high expression of IFN-ß correlated with tumor cell dormancy. Identification of this mechanism for controlling TRC dormancy by IFN-ß provides deeper insights into cancer-immune interaction and potential new cancer immunotherapeutic modalities.


Subject(s)
Interferon-beta/pharmacology , Neoplastic Stem Cells/cytology , STAT3 Transcription Factor/metabolism , Tumor Suppressor Protein p53/metabolism , Active Transport, Cell Nucleus , Animals , Cell Line, Tumor , Female , HEK293 Cells , Humans , Immune System , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Kynurenine/metabolism , MCF-7 Cells , Melanoma, Experimental/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, SCID , Neoplastic Stem Cells/drug effects , Phosphorylation , Reactive Oxygen Species/metabolism , Receptors, Aryl Hydrocarbon/metabolism , Serine/chemistry , Signal Transduction , Tyrosine/chemistry
16.
Nat Cell Biol ; 20(1): 21-27, 2018 01.
Article in English | MEDLINE | ID: mdl-29230018

ABSTRACT

CD8+ memory T (Tm) cells are fundamental for protective immunity against infections and cancers 1-5 . Metabolic activities are crucial in controlling memory T-cell homeostasis, but mechanisms linking metabolic signals to memory formation and survival remain elusive. Here we show that CD8+ Tm cells markedly upregulate cytosolic phosphoenolpyruvate carboxykinase (Pck1), the hub molecule regulating glycolysis, tricarboxylic acid cycle and gluconeogenesis, to increase glycogenesis via gluconeogenesis. The resultant glycogen is then channelled to glycogenolysis to generate glucose-6-phosphate and the subsequent pentose phosphate pathway (PPP) that generates abundant NADPH, ensuring high levels of reduced glutathione in Tm cells. Abrogation of Pck1-glycogen-PPP decreases GSH/GSSG ratios and increases levels of reactive oxygen species (ROS), leading to impairment of CD8+ Tm formation and maintenance. Importantly, this metabolic regulatory mechanism could be readily translated into more efficient T-cell immunotherapy in mouse tumour models.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Gene Expression Regulation, Neoplastic , Glucose/metabolism , Glycogen/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Melanoma, Experimental/genetics , Phosphoenolpyruvate Carboxykinase (GTP)/genetics , Skin Neoplasms/genetics , 3-Mercaptopropionic Acid/pharmacology , Adoptive Transfer , Animals , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/transplantation , Citric Acid Cycle/drug effects , Citric Acid Cycle/genetics , Citric Acid Cycle/immunology , Enzyme Inhibitors/pharmacology , Female , Gluconeogenesis/drug effects , Gluconeogenesis/genetics , Gluconeogenesis/immunology , Glucose/immunology , Glycogen/immunology , Glycolysis/drug effects , Glycolysis/genetics , Glycolysis/immunology , Homeostasis/immunology , Immunologic Memory , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/immunology , Melanoma, Experimental/drug therapy , Melanoma, Experimental/immunology , Melanoma, Experimental/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , NADP/immunology , NADP/metabolism , Pentose Phosphate Pathway/drug effects , Pentose Phosphate Pathway/genetics , Pentose Phosphate Pathway/immunology , Phosphoenolpyruvate Carboxykinase (GTP)/antagonists & inhibitors , Phosphoenolpyruvate Carboxykinase (GTP)/immunology , Reactive Oxygen Species/immunology , Reactive Oxygen Species/metabolism , Skin Neoplasms/drug therapy , Skin Neoplasms/immunology , Skin Neoplasms/metabolism
17.
Oncoimmunology ; 6(6): e1309487, 2017.
Article in English | MEDLINE | ID: mdl-28680743

ABSTRACT

Stem cell-like tumor-repopulating cells (TRCs) have a critical role in establishing a tumor immunosuppressive microenvironment. However, means to enhance antitumor immunity by disrupting TRCs are absent. Our previous studies have shown that tumor cell-derived microparticles (T-MPs) preferentially abrogate TRCs by delivering antitumor drugs into nuclei of TRCs. Here, we show that low dose irradiation (LDI) enhances the effect of cisplatin-packaging T-MPs (Cis-MPs) on TRCs, leading to inhibiting tumor growth in different tumor models. This antitumor effect is not due to the direct killing of tumor cells but is T cell-dependent and relies on macrophages for their efficacy. The underlying mechanism is involved in therapeutic reprograming macrophages from tumor-promotion to tumor-inhibition by disrupting TRCs and curtailing their vicious education on macrophages. These findings provide a novel strategy to reset macrophage polarization and confer their function more like M1 than M2 types with highly promising potential clinical applications.

18.
Nat Commun ; 8: 15207, 2017 05 10.
Article in English | MEDLINE | ID: mdl-28488695

ABSTRACT

Interactions with the immune system may lead tumorigenic cells into dormancy. However, the underlying molecular mechanism is poorly understood. Using a 3D fibrin gel model, we show that IFN-γ induces tumour-repopulating cells (TRCs) to enter dormancy through an indolamine 2,3-dioxygenase 1 (IDO1)-kynurenine (Kyn)-aryl hydrocarbon receptor (AhR)-p27 dependent pathway. Mechanistically, IFN-γ signalling triggers differentiated tumour cell apoptosis via STAT1; however, when IDO1 and AhR are highly expressed as in TRCs, IFN-γ results in IDO1/AhR-dependent p27 induction that prevents STAT1 signalling, thus suppressing the process of cell death and activating the dormancy program. Blocking the IDO/AhR metabolic circuitry not only abrogates IFN-γ-induced dormancy but also results in enhanced repression of tumour growth by IFN-γ-induced apoptosis of TRCs both in vitro and in vivo. These data present a previously unrecognized mechanism of inducing TRC dormancy by IFN-γ, suggesting a potential effective cancer immunotherapeutic modality through the combination of IFN-γ and IDO/AhR inhibitors.


Subject(s)
Apoptosis/physiology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Interferon-gamma/immunology , Kynurenine/metabolism , Neoplasms/pathology , Receptors, Aryl Hydrocarbon/metabolism , Animals , Cell Line, Tumor , Cell Proliferation/physiology , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Female , HEK293 Cells , Hep G2 Cells , Humans , MCF-7 Cells , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, SCID , STAT1 Transcription Factor/metabolism
19.
Oncoimmunology ; 6(3): e1282589, 2017.
Article in English | MEDLINE | ID: mdl-28405506

ABSTRACT

Exploiting gut mucosal immunity to design new antitumor vaccination strategy remains unexplored. Tumor cell-derived microparticles (T-MP) are natural biomaterials that are capable of delivering tumor antigens and innate signals to dendritic cells (DC) for tumor-specific T cell immunity. Here, we show that T-MPs by oral vaccination route effectively access and activate mucosal epithelium, leading to subsequent antitumor T cell responses. Oral vaccination of T-MPs generated potent inhibitory effect against the growth of B16 melanoma and CT26 colon cancer in mice, which required both T cell and DC activation. T-MPs, once entering intestinal lumen, were mainly taken up by ileac intestinal epithelial cells (IEC), where T-MPs activated NOD2 and its downstream MAPK and NF-κB, leading to chemokine releasing, including CCL2, from IECs to attract CD103+ CD11c+ DCs. Furthermore, ileac IECs could transcytose T-MPs to the basolateral site, where T-MPs were captured by those DCs for cross-presentation of loaded antigen contents. Elucidating these molecular and cellular mechanisms highlights T-MPs as a novel antitumor oral vaccination strategy with great potential of clinical applications.

20.
Biomaterials ; 113: 93-104, 2017 01.
Article in English | MEDLINE | ID: mdl-27810645

ABSTRACT

Nonmuscle-invasive bladder cancer (NMIBC) is treated with transurethral resection followed by intravesical chemotherapy. However, drug-resistant tumorigenic cells cannot be eliminated, leading to half of the treated cancers recur with increased stage and grade. Innovative approaches to enhance drug sensitivity and eradicate tumorigenic cells in NMIBC treatment are urgently needed. Here, we show that pre-instillation of tumor cell-derived microparticles (T-MP) as natural biomaterials markedly enhance the inhibitory effects of intravesical chemotherapy on growth and hematuria occurrence of orthotropic bladder cancer in mice. We provide evidence that T-MPs enter and increase the pH value of lysosomes from 4.6 to 5.6, leading to the migration of drug-loaded lysosomes along microtubule tracks toward the nucleus and discharging the drugs whereby for the entry of the nucleus. We propose that T-MPs may function as a potent sensitizer for augmenting NMIBC chemotherapy with unprecedented clinical benefits.


Subject(s)
Antineoplastic Agents/administration & dosage , Cell-Derived Microparticles/metabolism , Drug Carriers/metabolism , Lysosomes/metabolism , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/metabolism , Urinary Bladder/drug effects , Animals , Antineoplastic Agents/therapeutic use , Biocompatible Materials/metabolism , Cell Line, Tumor , Cell-Derived Microparticles/pathology , Female , Humans , Lysosomes/drug effects , Lysosomes/pathology , Mice , Mice, Inbred C57BL , Mice, SCID , Neoplasm Invasiveness/pathology , Neoplasm Invasiveness/prevention & control , Urinary Bladder/metabolism , Urinary Bladder/pathology , Urinary Bladder Neoplasms/pathology
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