RESUMO
BACKGROUND: Recent studies have discovered an emerging role of IL11 in various colitis-associated cancers, suggesting that IL11 mainly promotes tumor cell survival and proliferation in regulating tumorigenesis. Herein we aimed to reveal a novel function of IL-11 through STAT3 signaling in regulating tumor immune evasion. METHODS: AOM/DSS model in Il11-/- and Apcmin/+/Il11-/- mice were used to detect tumor growth and CD8+ T infiltration. STAT1/3 phosphorylation and MHC-I, CXCL9, H2-K1 and H2-D1 expression were detected in MC38 cells and intestine organoids treated with/without recombinant IL11 to explore effect of IL11/STAT3 signaling, with IL11 mutein used to competitively inhibit IL11 and rescue inhibited STAT1 activation. Correlation between IL11 and CD8+ T infiltration was analyzed using TIMER2.0 website. IL11 expression and survival prognosis was analyzed in clinical data of patient cohort from Nanfang Hospital. RESULTS: IL11 is highly expressed in CRC and indicates unfavorable prognosis. IL11 knockout increased CD8+ T cell infiltration and reduced intestinal and colon formation. Tumors were significantly suppressed while MHC-I and CXCL9 expression for CD8+ T infiltration were remarkably increased in the tumor tissues of Apcmin/+/Il11-/- mice or Il11-/- mice induced by AOM/DSS. IL11/STAT3 signaling downregulated MHC-I and CXCL9 by inhibiting IFNγ-induced STAT1 phosphorylation. IL11 mutein competitively inhibit IL11 to upregulate CXCL9 and MHC-I in tumor and attenuated tumor growth. CONCLUSIONS: This study ascribes for a new immunomodulatory role for IL11 during tumor development that is amenable to anti-cytokine based therapy of colon cancer.
Assuntos
Neoplasias do Colo , Interleucina-11 , Camundongos , Animais , Interleucina-11/metabolismo , Interleucina-11/farmacologia , Transdução de Sinais , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Citocinas/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Fator de Transcrição STAT3/metabolismoRESUMO
Dendritic cells (DCs) have a specialized endomembrane system capable of presenting exogenous antigens in the context of MHC class I (MHC-I) molecules. This process, named cross-presentation, is crucial to activate CD8+ T lymphocytes and initiate cytotoxic immune responses. In this report, we present an Agent-Based Model in combination with Ordinary Differential Equations with enough complexity to reproduce cross-presentation. The model embraces the secretory and endocytic pathways, in connection with the plasma membrane, the endoplasmic reticulum, and the cytosol. Key molecules required for cross-presentation were included as cargoes. In the simulations, the kinetics of MHC-I uptake and recycling, and cross-presentation accurately reproduced experimental values. The model proved to be a suitable tool to elaborate hypotheses and design experiments. In particular, the model predictions and the experimental results obtained indicate that the rate-limiting step in cross-presentation of soluble ovalbumin is MHC-I loading after proteasomal processing of the antigenic protein.
Assuntos
Apresentação de Antígeno , Apresentação Cruzada , Cinética , Ovalbumina , Linfócitos T CD8-PositivosRESUMO
Long-standing inflammatory bowel disease predisposes to the development of colorectal cancer (CRC). Interleukin (IL) -6, a pivotal link between chronic inflammation and tumor progression, has recently been recognized as a potential therapeutic target. The effect of IL-6 on proliferation and metastasis of CRC by activating the STAT3 pathway has been widely demonstrated in recent years, but few on mediating tumor immune evasion. In this study, we found that IL-6 was remarkably overexpressed in CRC and its elevation was associated with a poor prognosis. We studied CRC tumorigenesis in vivo by inoculating MC38 tumors and induced-CRC model via AOM/DSS (azoxymethane/dextransulfate sodium) in IL-6 deficient (IL-6-/-) and wild-type (WT) mice and found that IL-6-/- mice were less susceptible to develop tumors, compared to WT mice. We detected CD8+ T cells via immunofluorescence and found they exhibit high expression in tumor of IL-6-/- mice. High level of IL-6 was found in colitis model, with down-regulation of MHC-I molecules. In in vitro experiments, we found that IL-6 may act as a negative regulator in IFNγ-STAT1-MHC-I signaling. In addition, vivo trials also confirmed that MHC-I mRNA level was negatively related to the existence of IL-6. Furthermore, the blockade of IL-6 also activated CD8+T-cell accumulation and led to the high PD-L1 expression in CRC, which can sensitize animals to anti-PD-1 therapy. Our study provides a research basis for the significant role of IL-6 in tumor evasion and highlights a novel target to improve the efficacy of immunotherapy.
Assuntos
Neoplasias Colorretais , Interleucina-6/metabolismo , Animais , Linfócitos T CD8-Positivos/metabolismo , Neoplasias Colorretais/metabolismo , Imunoterapia , Camundongos , Transdução de Sinais , Evasão TumoralRESUMO
Cross-presentation by MHC class I molecules allows the detection of exogenous antigens by CD8+ T lymphocytes. This process is crucial to initiate cytotoxic immune responses against many pathogens (i.e., Toxoplasma gondii) and tumors. To achieve efficient cross-presentation, dendritic cells (DCs) have specialized endocytic pathways; however, the molecular effectors involved are poorly understood. In this work, we identify the small GTPase Rab22a as a key regulator of MHC-I trafficking and antigen cross-presentation by DCs. Our results demonstrate that Rab22a is recruited to DC endosomes and phagosomes, as well as to the vacuole containing T. gondii parasites. The silencing of Rab22a expression did not affect the uptake of exogenous antigens or parasite invasion, but it drastically reduced the intracellular pool and the recycling of MHC-I molecules. The knockdown of Rab22a also hampered the cross-presentation of soluble, particulate and T. gondii-associated antigens, but not the endogenous MHC-I antigen presentation through the classical secretory pathway. Our findings provide compelling evidence that Rab22a plays a central role in the MHC-I endocytic trafficking, which is crucial for efficient cross-presentation by DCs.
Assuntos
Apresentação de Antígeno , Proteínas de Transporte/metabolismo , Células Dendríticas/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Proteínas Nucleares/metabolismo , Toxoplasma/imunologia , Animais , Apresentação de Antígeno/genética , Apresentação de Antígeno/fisiologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/parasitologia , Linfócitos T CD8-Positivos/imunologia , Proteínas de Transporte/genética , Apresentação Cruzada , Proteínas de Ligação a DNA , Células Dendríticas/parasitologia , Endocitose , Endossomos/metabolismo , Endossomos/parasitologia , Regulação da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Camundongos , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Fagossomos/metabolismo , Fagossomos/parasitologia , Transporte Proteico , Proteínas de Ligação a RNA , Toxoplasma/fisiologia , Vacúolos/metabolismo , Vacúolos/parasitologiaRESUMO
Ischemic stroke is one of the leading causes of morbidity and mortality worldwide. The expression of major histocompatibility complex class I (MHC-I) molecules in the central nervous system, which are silenced under normal physiological conditions, have been reported to be induced by injury stimulation. The purpose of this study was to determine whether MHC-I molecules could serve as molecular targets for the acute phase of ischemic stroke and to assess whether a high-affinity peptide specific for MHC-I molecules could be applied in the near-infrared imaging of cerebral ischemic mice. Quantitative real-time PCR and Western blotting were used to detect the expression of MHC-I molecules in two mouse models of cerebral ischemic stroke and an in vitro model of ischemia. The NetMHC 4.0 server was used to screen a high-affinity peptide specific for mouse MHC-I molecules. The Rosetta program was used to identify the specificity and affinity of the screened peptide (histocompatibility-2 binding peptide, H2BP). The results demonstrated that MHC-I molecules could serve as molecular targets for the acute phase of ischemic stroke. Cy5.5-H2BP molecular probes could be applied in the near-infrared imaging of cerebral ischemic mice. Research on the expression of MHC-I molecules in the acute phase after ischemia and MHC-I-targeted imaging may not only be helpful for understanding the mechanism of ischemic and hypoxic brain injury and repair but also has potential application value in the imaging of ischemic stroke.
Assuntos
Sistema Nervoso Central/diagnóstico por imagem , Sistema Nervoso Central/patologia , Antígenos de Histocompatibilidade Classe I/análise , Isquemia/patologia , Técnicas de Diagnóstico Molecular/métodos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/patologia , Animais , Western Blotting , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Camundongos , Modelos Biológicos , Técnicas de Sonda Molecular , Reação em Cadeia da Polimerase em Tempo RealRESUMO
In this review, I summarize some of the early research on NK cell biology and function that led to the discovery of a totally new receptor system for polymorphic MHC class I molecules. That NK cells both could recognize and kill tumor cells but also normal hematopoietic cells through expression of MHC class I molecules found a unifying explanation in the "missing self" hypothesis. This initiated a whole new area of leukocyte receptor research. The common underlying mechanism was that NK cells expressed receptors that were inhibited by recognition of unmodified "self" MHC-I molecules. This could explain both the killing of tumor cells with poor expression of MHC-I molecules and hybrid resistance, i.e., that F1 hybrid mice sometimes could reject parental bone marrow cells. However, a contrasting phenomenon termed allogeneic lymphocyte cytotoxicity in rats gave strong evidence that some of these receptors were activated rather than inhibited by recognition of polymorphic MHC-I. This was soon followed by molecular identification of both inhibitory and stimulatory Ly49 receptors in mice and rats and killer cell immunoglobulin-like receptors in humans that could be either inhibited or activated when recognizing their cognate MHC-I ligand. Since most of these receptors now have been molecularly characterized, their ligands and the intracellular pathways leading to activation or inhibition identified, we still lack a more complete understanding of how the repertoire of activating and inhibitory receptors is formed and how interactions between these receptors for MHC-I molecules on a single NK cell are integrated to generate a productive immune response. Although several NK receptor systems have been characterized that recognize MHC-I or MHC-like molecules, I here concentrate on the repertoires of NK receptors encoded by the natural killer cell gene complex and designed to recognize polymorphic MHC-I molecules in rodents, i.e., Ly49 (KLRA) receptors.