RESUMO
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.
Assuntos
Anemia , Neoplasias , Humanos , Estudos Prospectivos , Qualidade de Vida , Anemia/complicações , Anemia/terapia , Neoplasias/complicações , Neoplasias/terapia , ImunoterapiaRESUMO
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.
Assuntos
Imunoterapia/métodos , Interferon Tipo I/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Animais , Fibroblastos Associados a Câncer/imunologia , Terapia Combinada , Células Dendríticas/imunologia , Células Endoteliais/imunologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Interferon Tipo I/biossíntese , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Macrófagos/imunologia , Camundongos , Modelos Imunológicos , Células Supressoras Mieloides/imunologia , Neutrófilos/imunologia , Terapia Viral Oncolítica , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Receptores Toll-Like/agonistas , Microambiente Tumoral/imunologiaRESUMO
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.
Assuntos
Embrião de Mamíferos/patologia , Neoplasias/patologia , Neoplasias/prevenção & controle , Macrófagos Associados a Tumor/patologia , Glucose/metabolismo , Humanos , Metabolismo dos Lipídeos , Neoplasias/metabolismo , Análise de Célula ÚnicaRESUMO
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.
Assuntos
Neoplasias/metabolismo , Microambiente Tumoral/fisiologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/fisiologia , Animais , Humanos , Imunidade Inata/fisiologia , Transdução de Sinais/fisiologiaRESUMO
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.
Assuntos
Células-Tronco Embrionárias , Hematopoese Extramedular/genética , Células-Tronco Hematopoéticas , Neoplasias/genética , Humanos , Terapia de Imunossupressão , Neoplasias/patologia , Estresse Fisiológico/genéticaRESUMO
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.
Assuntos
Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação Neoplásica da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos C57BLRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/genética , Quercetina/farmacologia , Antracenos/farmacologia , Caspases/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Mutação , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
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.
Assuntos
Micropartículas Derivadas de Células/imunologia , Inflamação , Neoplasias Pulmonares/patologia , Macrófagos/imunologia , Metástase Neoplásica/imunologia , Animais , Micropartículas Derivadas de Células/patologia , Feminino , Pulmão/citologia , Pulmão/imunologia , Neoplasias Pulmonares/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microambiente Tumoral/imunologiaRESUMO
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.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Epigênese Genética/fisiologia , Fibrina/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Células A549 , Animais , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Dioxigenases , Regulação para Baixo/fisiologia , Epigenômica/métodos , Feminino , Células Hep G2 , Humanos , Mecanotransdução Celular/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCIDRESUMO
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.
RESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Cloroquina/farmacologia , Imunoterapia/métodos , Macrófagos/citologia , Macrófagos/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Linhagem Celular Tumoral , Feminino , Glicólise/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos Transgênicos , NF-kappa B/metabolismo , Células RAW 264.7 , Canais de Potencial de Receptor Transitório/metabolismo , Microambiente Tumoral/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
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.
Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Cinurenina/farmacologia , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/efeitos dos fármacos , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Humanos , Interferon gama/imunologia , Camundongos , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologiaRESUMO
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.
Assuntos
Interferon beta/farmacologia , Células-Tronco Neoplásicas/citologia , Fator de Transcrição STAT3/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Sistema Imunitário , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Células MCF-7 , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Serina/química , Transdução de Sinais , Tirosina/químicaRESUMO
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.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Regulação Neoplásica da Expressão Gênica , Glucose/metabolismo , Glicogênio/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Melanoma Experimental/genética , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Neoplasias Cutâneas/genética , Ácido 3-Mercaptopropiônico/farmacologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/transplante , Ciclo do Ácido Cítrico/efeitos dos fármacos , Ciclo do Ácido Cítrico/genética , Ciclo do Ácido Cítrico/imunologia , Inibidores Enzimáticos/farmacologia , Feminino , Gluconeogênese/efeitos dos fármacos , Gluconeogênese/genética , Gluconeogênese/imunologia , Glucose/imunologia , Glicogênio/imunologia , Glicólise/efeitos dos fármacos , Glicólise/genética , Glicólise/imunologia , Homeostase/imunologia , Memória Imunológica , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NADP/imunologia , NADP/metabolismo , Via de Pentose Fosfato/efeitos dos fármacos , Via de Pentose Fosfato/genética , Via de Pentose Fosfato/imunologia , Fosfoenolpiruvato Carboxiquinase (GTP)/antagonistas & inibidores , Fosfoenolpiruvato Carboxiquinase (GTP)/imunologia , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismoRESUMO
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.
RESUMO
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.
Assuntos
Apoptose/fisiologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Interferon gama/imunologia , Cinurenina/metabolismo , Neoplasias/patologia , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Células HEK293 , Células Hep G2 , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Fator de Transcrição STAT1/metabolismoRESUMO
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.
RESUMO
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.