RESUMEN
Malignancy can be suppressed by the immune system. However, the classes of immunosurveillance responses and their mode of tumor sensing remain incompletely understood. Here, we show that although clear cell renal cell carcinoma (ccRCC) was infiltrated by exhaustion-phenotype CD8+ T cells that negatively correlated with patient prognosis, chromophobe RCC (chRCC) had abundant infiltration of granzyme A-expressing intraepithelial type 1 innate lymphoid cells (ILC1s) that positively associated with patient survival. Interleukin-15 (IL-15) promoted ILC1 granzyme A expression and cytotoxicity, and IL-15 expression in chRCC tumor tissue positively tracked with the ILC1 response. An ILC1 gene signature also predicted survival of a subset of breast cancer patients in association with IL-15 expression. Notably, ILC1s directly interacted with cancer cells, and IL-15 produced by cancer cells supported the expansion and anti-tumor function of ILC1s in a murine breast cancer model. Thus, ILC1 sensing of cancer cell IL-15 defines an immunosurveillance mechanism of epithelial malignancies.
Asunto(s)
Neoplasias de la Mama , Interleucina-15/metabolismo , Animales , Neoplasias de la Mama/genética , Linfocitos T CD8-positivos , Femenino , Granzimas , Humanos , Inmunidad Innata , Linfocitos , RatonesRESUMEN
Tumors develop by invoking a supportive environment characterized by aberrant angiogenesis and infiltration of tumor-associated macrophages (TAMs). In a transgenic model of breast cancer, we found that TAMs localized to the tumor parenchyma and were smaller than mammary tissue macrophages. TAMs had low activity of the metabolic regulator mammalian/mechanistic target of rapamycin complex 1 (mTORC1), and depletion of negative regulator of mTORC1 signaling, tuberous sclerosis complex 1 (TSC1), in TAMs inhibited tumor growth in a manner independent of adaptive lymphocytes. Whereas wild-type TAMs exhibited inflammatory and angiogenic gene expression profiles, TSC1-deficient TAMs had a pro-resolving phenotype. TSC1-deficient TAMs relocated to a perivascular niche, depleted protein C receptor (PROCR)-expressing endovascular endothelial progenitor cells, and rectified the hyperpermeable blood vasculature, causing tumor tissue hypoxia and cancer cell death. TSC1-deficient TAMs were metabolically active and effectively eliminated PROCR-expressing endothelial cells in cell competition experiments. Thus, TAMs exhibit a TSC1-dependent mTORC1-low state, and increasing mTORC1 signaling promotes a pro-resolving state that suppresses tumor growth, defining an innate immune tumor suppression pathway that may be exploited for cancer immunotherapy.
Asunto(s)
Células Progenitoras Endoteliales , Proteínas Supresoras de Tumor , Animales , Humanos , Serina-Treonina Quinasas TOR/metabolismo , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Macrófagos Asociados a Tumores/metabolismo , Células Progenitoras Endoteliales/metabolismo , Receptor de Proteína C Endotelial , Diana Mecanicista del Complejo 1 de la Rapamicina , Neovascularización Patológica , MamíferosRESUMEN
Small immune complexes cause type III hypersensitivity reactions that frequently result in tissue injury. The responsible mechanisms, however, remain unclear and differ depending on target organs. Here, we identify a kidney-specific anatomical and functional unit, formed by resident macrophages and peritubular capillary endothelial cells, which monitors the transport of proteins and particles ranging from 20 to 700 kDa or 10 to 200 nm into the kidney interstitium. Kidney-resident macrophages detect and scavenge circulating immune complexes "pumped" into the interstitium via trans-endothelial transport and trigger a FcγRIV-dependent inflammatory response and the recruitment of monocytes and neutrophils. In addition, FcγRIV and TLR pathways synergistically "super-activate" kidney macrophages when immune complexes contain a nucleic acid. These data identify a physiological function of tissue-resident kidney macrophages and a basic mechanism by which they initiate the inflammatory response to small immune complexes in the kidney.
Asunto(s)
Enfermedades del Complejo Inmune/inmunología , Riñón/citología , Riñón/inmunología , Macrófagos/inmunología , Animales , Complejo Antígeno-Anticuerpo , Células Endoteliales , Macrófagos/citología , Ratones Endogámicos C57BL , Microscopía Inmunoelectrónica , Monocitos/citología , Monocitos/inmunología , Neutrófilos/citología , Neutrófilos/inmunología , Receptores de IgG/inmunologíaRESUMEN
Aerobic glycolysis-the Warburg effect-converts glucose to lactate via the enzyme lactate dehydrogenase A (LDHA) and is a metabolic feature of effector T cells. Cells generate ATP through various mechanisms and Warburg metabolism is comparatively an energy-inefficient glucose catabolism pathway. Here, we examined the effect of ATP generated via aerobic glycolysis in antigen-driven T cell responses. Cd4CreLdhafl/fl mice were resistant to Th17-cell-mediated experimental autoimmune encephalomyelitis and exhibited defective T cell activation, migration, proliferation, and differentiation. LDHA deficiency crippled cellular redox balance and inhibited ATP production, diminishing PI3K-dependent activation of Akt kinase and thereby phosphorylation-mediated inhibition of Foxo1, a transcriptional repressor of T cell activation programs. Th17-cell-specific expression of an Akt-insensitive Foxo1 recapitulated the defects seen in Cd4CreLdhafl/fl mice. Induction of LDHA required PI3K signaling and LDHA deficiency impaired PI3K-catalyzed PIP3 generation. Thus, Warburg metabolism augments glycolytic ATP production, fueling a PI3K-centered positive feedback regulatory circuit that drives effector T cell responses.
Asunto(s)
Adenosina Trifosfato/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Transducción de Señal/fisiología , Células Th17/metabolismo , Animales , Diferenciación Celular/fisiología , Línea Celular , Proliferación Celular/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Glucosa/metabolismo , Enfermedad del Almacenamiento de Glucógeno/metabolismo , Glucólisis/fisiología , L-Lactato Deshidrogenasa/deficiencia , L-Lactato Deshidrogenasa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
In systemic lupus erythematosus (SLE) loss of immune tolerance, autoantibody production and immune complex deposition are required but not sufficient for organ damage1. How inflammatory signals are initiated and amplified in the setting of autoimmunity remains elusive. Here, we set out to dissect layers and hierarchies of autoimmune kidney inflammation in order to identify tissue-specific cellular hubs that amplify auto-inflammatory responses. Using high-resolution single-cell profiling of kidney immune and parenchymal cells, in combination with antibody blocking and genetic deficiency, we show that tissue-resident NKp46+ innate lymphoid cells (ILC) are crucial signal amplifiers of disease-associated macrophage expansion and epithelial cell injury in lupus nephritis, downstream of autoantibody production. NKp46 signaling in a distinct subset of ILC1 instructed an unconventional immune-regulatory transcriptional program, which included the expression of the myeloid cell growth factor CSF2. CSF2 production by NKp46+ ILC promoted the population expansion of monocyte-derived macrophages. Blockade of the NKp46 receptor (using the antibody mNCR1.152) or genetic deficiency of NKp46 abrogated epithelial cell injury. The same cellular and molecular patterns were operative in human lupus nephritis. Our data support that NKp46+ ILC1 promote parenchymal cell injury by granting monocyte-derived macrophages access to epithelial cell niches. NKp46 activation in ILC1 thus constitutes a previously unrecognized, critical tissue rheostat that amplifies organ damage in autoimmune hosts, with broad implications for inflammatory pathologies and therapies.
RESUMEN
Natural killer (NK) cells are cytotoxic type 1 innate lymphoid cells (ILCs) that defend against viruses and mediate anti-tumor responses, yet mechanisms controlling their development and function remain incompletely understood. We hypothesized that the abundantly expressed microRNA-142 (miR-142) is a critical regulator of type 1 ILC biology. Interleukin-15 (IL-15) signaling induced miR-142 expression, whereas global and ILC-specific miR-142-deficient mice exhibited a cell-intrinsic loss of NK cells. Death of NK cells resulted from diminished IL-15 receptor signaling within miR-142-deficient mice, likely via reduced suppressor of cytokine signaling-1 (Socs1) regulation by miR-142-5p. ILCs persisting in Mir142-/- mice demonstrated increased expression of the miR-142-3p target αV integrin, which supported their survival. Global miR-142-deficient mice exhibited an expansion of ILC1-like cells concurrent with increased transforming growth factor-ß (TGF-ß) signaling. Further, miR-142-deficient mice had reduced NK-cell-dependent function and increased susceptibility to murine cytomegalovirus (MCMV) infection. Thus, miR-142 critically integrates environmental cues for proper type 1 ILC homeostasis and defense against viral infection.
Asunto(s)
Homeostasis/inmunología , Inmunidad Innata/inmunología , Linfocitos/inmunología , MicroARNs/inmunología , Animales , Línea Celular , Femenino , Células HEK293 , Humanos , Células Asesinas Naturales/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Muromegalovirus/inmunología , Células 3T3 NIH , Receptores de Interleucina-15/inmunología , Transducción de Señal/inmunología , Proteínas Supresoras de la Señalización de Citocinas/inmunología , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
The functions of Nr4a1-dependent Ly6C(low) monocytes remain enigmatic. We show that they are enriched within capillaries and scavenge microparticles from their lumenal side in a steady state. In the kidney cortex, perturbation of homeostasis by a TLR7-dependent nucleic acid "danger" signal, which may signify viral infection or local cell death, triggers Gαi-dependent intravascular retention of Ly6C(low) monocytes by the endothelium. Then, monocytes recruit neutrophils in a TLR7-dependent manner to mediate focal necrosis of endothelial cells, whereas the monocytes remove cellular debris. Prevention of Ly6C(low) monocyte development, crawling, or retention in Nr4a1(-/-), Itgal(-/-), and Tlr7(host-/-BM+/+) and Cx3cr1(-/-) mice, respectively, abolished neutrophil recruitment and endothelial killing. Prevention of neutrophil recruitment in Tlr7(host+/+BM-/-) mice or by neutrophil depletion also abolished endothelial cell necrosis. Therefore, Ly6C(low) monocytes are intravascular housekeepers that orchestrate the necrosis by neutrophils of endothelial cells that signal a local threat sensed via TLR7 followed by the in situ phagocytosis of cellular debris.
Asunto(s)
Células Endoteliales/metabolismo , Monitorización Inmunológica , Monocitos/inmunología , Animales , Moléculas de Adhesión Celular/metabolismo , Micropartículas Derivadas de Células , Endotelio Vascular/citología , Endotelio Vascular/inmunología , Humanos , Inflamación , Molécula 1 de Adhesión Intercelular/metabolismo , Riñón/irrigación sanguínea , Riñón/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Ratones , Monocitos/metabolismo , Neutrófilos/inmunología , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Receptores de Quimiocina/metabolismoRESUMEN
Cellular transformation induces phenotypically diverse populations of tumour-infiltrating T cells1-5, and immune checkpoint blockade therapies preferentially target T cells that recognize cancer cell neoantigens6,7. Yet, how other classes of tumour-infiltrating T cells contribute to cancer immunosurveillance remains elusive. Here, in a survey of T cells in mouse and human malignancies, we identified a population of αß T cell receptor (TCR)-positive FCER1G-expressing innate-like T cells with high cytotoxic potential8 (ILTCKs). These cells were broadly reactive to unmutated self-antigens, arose from distinct thymic progenitors following early encounter with cognate antigens, and were continuously replenished by thymic progenitors during tumour progression. Notably, expansion and effector differentiation of intratumoural ILTCKs depended on interleukin-15 (IL-15) expression in cancer cells, and inducible activation of IL-15 signalling in adoptively transferred ILTCK progenitors suppressed tumour growth. Thus, the antigen receptor self-reactivity, unique ontogeny, and distinct cancer cell-sensing mechanism distinguish ILTCKs from conventional cytotoxic T cells, and define a new class of tumour-elicited immune response.
Asunto(s)
Inmunidad Innata , Interleucina-15 , Neoplasias , Animales , Diferenciación Celular , Ratones , Neoplasias/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T Citotóxicos/metabolismoRESUMEN
Cancer arises from malignant cells that exist in dynamic multilevel interactions with the host tissue. Cancer therapies aiming to directly kill cancer cells, including oncogene-targeted therapy and immune-checkpoint therapy that revives tumour-reactive cytotoxic T lymphocytes, are effective in some patients1,2, but acquired resistance frequently develops3,4. An alternative therapeutic strategy aims to rectify the host tissue pathology, including abnormalities in the vasculature that foster cancer progression5,6; however, neutralization of proangiogenic factors such as vascular endothelial growth factor A (VEGFA) has had limited clinical benefits7,8. Here, following the finding that transforming growth factor-ß (TGF-ß) suppresses T helper 2 (TH2)-cell-mediated cancer immunity9, we show that blocking TGF-ß signalling in CD4+ T cells remodels the tumour microenvironment and restrains cancer progression. In a mouse model of breast cancer resistant to immune-checkpoint or anti-VEGF therapies10,11, inducible genetic deletion of the TGF-ß receptor II (TGFBR2) in CD4+ T cells suppressed tumour growth. For pharmacological blockade, we engineered a bispecific receptor decoy by attaching the TGF-ß-neutralizing TGFBR2 extracellular domain to ibalizumab, a non-immunosuppressive CD4 antibody12,13, and named it CD4 TGF-ß Trap (4T-Trap). Compared with a non-targeted TGF-ß-Trap, 4T-Trap selectively inhibited TH cell TGF-ß signalling in tumour-draining lymph nodes, causing reorganization of tumour vasculature and cancer cell death, a process dependent on the TH2 cytokine interleukin-4 (IL-4). Notably, the 4T-Trap-induced tumour tissue hypoxia led to increased VEGFA expression. VEGF inhibition enhanced the starvation-triggered cancer cell death and amplified the antitumour effect of 4T-Trap. Thus, targeted TGF-ß signalling blockade in helper T cells elicits an effective tissue-level cancer defence response that can provide a basis for therapies directed towards the cancer environment.
Asunto(s)
Neoplasias de la Mama/terapia , Inmunoterapia , Transducción de Señal/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/inmunología , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Muerte Celular/efectos de los fármacos , Hipoxia de la Célula , Línea Celular Tumoral , Femenino , Células HEK293 , Humanos , Interleucina-4/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Masculino , Ratones , Receptor Tipo II de Factor de Crecimiento Transformador beta/química , Receptor Tipo II de Factor de Crecimiento Transformador beta/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Factor de Crecimiento Transformador beta/inmunología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The immune system uses two distinct defence strategies against infections: microbe-directed pathogen destruction characterized by type 1 immunity1, and host-directed pathogen containment exemplified by type 2 immunity in induction of tissue repair2. Similar to infectious diseases, cancer progresses with self-propagating cancer cells inflicting host-tissue damage. The immunological mechanisms of cancer cell destruction are well defined3-5, but whether immune-mediated cancer cell containment can be induced remains poorly understood. Here we show that depletion of transforming growth factor-ß receptor 2 (TGFBR2) in CD4+ T cells, but not CD8+ T cells, halts cancer progression as a result of tissue healing and remodelling of the blood vasculature, causing cancer cell hypoxia and death in distant avascular regions. Notably, the host-directed protective response is dependent on the T helper 2 cytokine interleukin-4 (IL-4), but not the T helper 1 cytokine interferon-γ (IFN-γ). Thus, type 2 immunity can be mobilized as an effective tissue-level defence mechanism against cancer.
Asunto(s)
Neoplasias/inmunología , Neoplasias/patología , Transducción de Señal/inmunología , Células Th2/inmunología , Factor de Crecimiento Transformador beta/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Muerte Celular/efectos de los fármacos , Hipoxia de la Célula , Línea Celular , Progresión de la Enfermedad , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Interferón gamma/inmunología , Interleucina-4/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Neoplasias/irrigación sanguínea , Neoplasias/metabolismo , Receptor Tipo II de Factor de Crecimiento Transformador beta/deficiencia , Transducción de Señal/efectos de los fármacos , Células del Estroma/citología , Células del Estroma/inmunología , Células Th2/metabolismo , Factor de Crecimiento Transformador beta/antagonistas & inhibidoresRESUMEN
Innate lymphocytes play an important role in maintaining tissue homeostasis at steady state and during inflammation. The population of innate lymphocytes is incredibly diverse and heterogeneous with the successive identification of new subsets including innate lymphoid cells that arise from progenitors distinct from those of natural killer cells. Although generally considered as T helper-like lymphocytes, innate lymphoid cells with cytotoxic potential can be identified in many tissues. The tissue-resident cytotoxic innate lymphocytes derived from innate lymphoid cell and/or natural killer cell lineages are well positioned in sensing malignant transformation and initiating antitumor immunity. This review provides an overview of innate lymphocyte biology and discuss their roles in tumor immunosurveillance.
Asunto(s)
Citotoxicidad Inmunológica , Inmunidad Innata , Vigilancia Inmunológica , Subgrupos Linfocitarios/inmunología , Tejido Linfoide/inmunología , Neoplasias/inmunología , Neoplasias/patología , Animales , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/metabolismo , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Subgrupos Linfocitarios/metabolismo , Tejido Linfoide/metabolismo , Especificidad de Órganos/inmunología , Microambiente TumoralRESUMEN
Intravital microscopy is an invaluable tool to study in real time the dynamic behavior of leukocytes in vivo. We describe herein a simple protocol for time-lapse imaging of tissue-resident macrophages in intact kidney, liver, and spleen in live mice. This method can be used in any commercially available inverted confocal microscope, doesn't require expensive lasers or optics, exhibits minimal organ perturbation, photo bleaching, or phototoxicity, and, hence, it enables the study of tissue-resident macrophages in situ and in vivo under steady state and inflammation.
Asunto(s)
Ácido Hipocloroso , Microscopía Intravital , Animales , Ratones , Monitorización Inmunológica , Inflamación , MacrófagosRESUMEN
Infection triggers expansion and effector differentiation of T cells specific for microbial antigens in association with metabolic reprograming. We found that the glycolytic enzyme lactate dehydrogenase A (LDHA) is induced in CD8+ T effector cells through phosphoinositide 3-kinase (PI3K) signaling. In turn, ablation of LDHA inhibits PI3K-dependent phosphorylation of Akt and its transcription factor target Foxo1, causing defective antimicrobial immunity. LDHA deficiency cripples cellular redox control and diminishes adenosine triphosphate (ATP) production in effector T cells, resulting in attenuated PI3K signaling. Thus, nutrient metabolism and growth factor signaling are highly integrated processes, with glycolytic ATP serving as a rheostat to gauge PI3K-Akt-Foxo1 signaling in the control of T cell immunity. Such a bioenergetic mechanism for the regulation of signaling may explain the Warburg effect.