RESUMEN
Presence of TGFß in the tumor microenvironment is one of the most relevant cancer immune-escape mechanisms. TGFß is secreted in an inactive form, and its activation within the tumor may depend on different cell types and mechanisms than its production. Here we show in mouse melanoma and breast cancer models that regulatory T (Treg) cells expressing the ß8 chain of αvß8 integrin (Itgß8) are the main cell type in the tumors that activates TGFß, produced by the cancer cells and stored in the tumor micro-environment. Itgß8 ablation in Treg cells impairs TGFß signalling in intra-tumoral T lymphocytes but not in the tumor draining lymph nodes. Successively, the effector function of tumor infiltrating CD8+ T lymphocytes strengthens, leading to efficient control of tumor growth. In cancer patients, anti-Itgß8 antibody treatment elicits similar improved cytotoxic T cell activation. Thus, this study reveals that Treg cells work in concert with cancer cells to produce bioactive-TGFß and to create an immunosuppressive micro-environment.
Asunto(s)
Integrinas/inmunología , Neoplasias/inmunología , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta/inmunología , Animales , Femenino , Humanos , Integrinas/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias/genética , Microambiente TumoralRESUMEN
OBJECTIVES: To better understand how immune responses may be harnessed against breast cancer, we investigated which immune cell types and signalling pathways are required for spontaneous control of a mouse model of mammary adenocarcinoma. METHODS: The NOP23 mammary adenocarcinoma cell line expressing epitopes derived from the ovalbumin model antigen is spontaneously controlled when orthotopically engrafted in syngeneic C57BL/6 mice. We combined this breast cancer model with antibody-mediated depletion of lymphocytes and with mutant mice affected in interferon (IFN) or type 1 conventional dendritic cell (cDC1) responses. We monitored tumor growth and immune infiltration including the activation of cognate ovalbumin-specific T cells. RESULTS: Breast cancer immunosurveillance required cDC1, NK/NK T cells, conventional CD4+ T cells and CD8+ cytotoxic T lymphocytes (CTLs). cDC1 were required constitutively, but especially during T-cell priming. In tumors, cDC1 were interacting simultaneously with CD4+ T cells and tumor-specific CTLs. cDC1 expression of the XCR1 chemokine receptor and of the T-cell-attracting or T-cell-activating cytokines CXCL9, IL-12 and IL-15 was dispensable for tumor rejection, whereas IFN responses were necessary, including cDC1-intrinsic signalling by STAT1 and IFN-γ but not type I IFN (IFN-I). cDC1 and IFNs promoted CD4+ and CD8+ T-cell infiltration, terminal differentiation and effector functions. In breast cancer patients, high intratumor expression of genes specific to cDC1, CTLs, CD4+ T cells or IFN responses is associated with a better prognosis. CONCLUSION: Interferons and cDC1 are critical for breast cancer immunosurveillance. IFN-γ plays a prominent role over IFN-I in licensing cDC1 for efficient T-cell activation.
RESUMEN
Claudin-low breast cancers are aggressive tumors defined by the low expression of key components of cellular junctions, associated with mesenchymal and stemness features. Although they are generally considered as the most primitive breast malignancies, their histogenesis remains elusive. Here we show that this molecular subtype of breast cancers exhibits a significant diversity, comprising three main subgroups that emerge from unique evolutionary processes. Genetic, gene methylation and gene expression analyses reveal that two of the subgroups relate, respectively, to luminal breast cancers and basal-like breast cancers through the activation of an EMT process over the course of tumor progression. The third subgroup is closely related to normal human mammary stem cells. This unique subgroup of breast cancers shows a paucity of genomic aberrations and a low frequency of TP53 mutations, supporting the emerging notion that the intrinsic properties of the cell-of-origin constitute a major determinant of the genetic history of tumorigenesis.
Asunto(s)
Neoplasias de la Mama/metabolismo , Claudinas/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinogénesis/genética , Carcinogénesis/patología , Diferenciación Celular , Línea Celular Tumoral , Variaciones en el Número de Copia de ADN/genética , Metilación de ADN/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Heterogeneidad Genética , Genoma Humano , Humanos , Ploidias , Transducción de Señal/genéticaRESUMEN
Transforming growth factor-ß (TGF-ß) is a major immunosuppressive cytokine that maintains immune homeostasis and prevents autoimmunity through its antiproliferative and anti-inflammatory properties in various immune cell types. We provide genetic, pharmacologic, and biochemical evidence that a critical target of TGF-ß signaling in mouse and human natural killer (NK) cells is the serine and threonine kinase mTOR (mammalian target of rapamycin). Treatment of mouse or human NK cells with TGF-ß in vitro blocked interleukin-15 (IL-15)-induced activation of mTOR. TGF-ß and the mTOR inhibitor rapamycin both reduced the metabolic activity and proliferation of NK cells and reduced the abundances of various NK cell receptors and the cytotoxic activity of NK cells. In vivo, constitutive TGF-ß signaling or depletion of mTOR arrested NK cell development, whereas deletion of the TGF-ß receptor subunit TGF-ßRII enhanced mTOR activity and the cytotoxic activity of the NK cells in response to IL-15. Suppression of TGF-ß signaling in NK cells did not affect either NK cell development or homeostasis; however, it enhanced the ability of NK cells to limit metastases in two different tumor models in mice. Together, these results suggest that the kinase mTOR is a crucial signaling integrator of pro- and anti-inflammatory cytokines in NK cells. Moreover, we propose that boosting the metabolic activity of antitumor lymphocytes could be an effective strategy to promote immune-mediated tumor suppression.
Asunto(s)
Inmunidad Celular , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Transducción de Señal/inmunología , Serina-Treonina Quinasas TOR/inmunología , Factor de Crecimiento Transformador beta/inmunología , Animales , Humanos , Interleucina-15/inmunología , Células Asesinas Naturales/patología , Ratones , Ratones Noqueados , Neoplasias Experimentales/genética , Neoplasias Experimentales/inmunología , Serina-Treonina Quinasas TOR/genética , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Intestinal DCs orchestrate gut immune homeostasis by dampening proinflammatory T-cell responses and inducing anti-inflammatory IgA responses. Although no specific DC subset has been strictly assigned so far to govern IgA response, some candidate subsets emerge. In particular, plasmacytoid DCs (pDCs), which notoriously promote anti-viral immunity and T-cell tolerance to innocuous antigens (Ags), contribute to IgA induction in response to intestinal viral infection and promote T-cell-independent IgA responses in vitro. Here, using two transgenic mouse models, we show that neither short-term nor long-term pDC depletion alters IgA class switch recombination in Peyer's patches and frequency of IgA plasma cells in intestinal mucosa at steady state, even in the absence of T-cell help. In addition, pDCs are dispensable for induction of intestinal IgA plasma cells in response to oral immunization with T-cell-dependent or T-cell-independent Ags, and are not required for proliferation and IgA switch of Ag-specific B cells in GALT. These results show that pDCs are dispensable for noninfectious IgA responses, and suggest that various DC subsets may play redundant roles in the control of intestinal IgA responses.
Asunto(s)
Linfocitos B/inmunología , Células Dendríticas/inmunología , Inmunoglobulina A/metabolismo , Mucosa Intestinal/inmunología , Células Plasmáticas/inmunología , Animales , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Homeostasis , Humanos , Tolerancia Inmunológica , Inmunización , Cambio de Clase de Inmunoglobulina , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Linfocitos T/inmunología , Factor de Transcripción 4RESUMEN
Plasmacytoid dendritic cells (pDC) are key regulators of antiviral immunity. In previous studies, we reported that pDC-infiltrating human primary breast tumors represent an independent prognostic factor associated with poor outcome. To understand this negative impact of tumor-associated pDC (TApDC), we developed an orthotopic murine mammary tumor model that closely mimics the human pathology, including pDC and regulatory T cell (Treg) infiltration. We showed that TApDC are mostly immature and maintain their ability to internalize antigens in vivo and to activate CD4(+) T cells. Most importantly, TApDC were specifically altered for cytokine production in response to Toll-like receptor (TLR)-9 ligands in vitro while preserving unaltered response to TLR7 ligands (TLR7L). In vivo pDC depletion delayed tumor growth, showing that TApDC provide an immune-subversive environment, most likely through Treg activation, thus favoring tumor progression. However, in vivo intratumoral administration of TLR7L led to TApDC activation and displayed a potent curative effect. Depletion of pDC and type I IFN neutralization prevented TLR7L antitumoral effect. Our results establish a direct contribution of TApDC to primary breast tumor progression and rationalize the application of TLR7 ligands to restore TApDC activation in breast cancer. Cancer Res; 73(15); 4629-40. ©2013 AACR.
Asunto(s)
Células Dendríticas/inmunología , Activación de Linfocitos/inmunología , Neoplasias Mamarias Experimentales/inmunología , Glicoproteínas de Membrana/inmunología , Receptor Toll-Like 7/inmunología , Animales , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Femenino , Ligandos , Prueba de Cultivo Mixto de Linfocitos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias Mamarias Experimentales/metabolismo , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Receptor Toll-Like 7/metabolismoRESUMEN
Viruses represent an important cause of cancer in humans: infections are estimated to account for close to one cancer case out of five.With the ongoing discovery of new infectious agents, this number should be raising in the near future. In 2006, the discovery of a new _-retrovirus in prostate cancer biopsies launched an intense research activity: could this new xenotropic MLV-related virus (XMRV) be the cause of prostate cancer? Five years later, the initial enthusiasm of retrovirologists has dramatically diminished. One by one, arguments favouring the hypothesis of human infection with XMRV are being refuted. The aim of this review article is to present the discovery of XMRV and to analyze recent data arguing against its existence in humans. A synthetic interpretation of XMRV literature will then be suggested.