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1.
Sci Immunol ; 8(90): eabo5558, 2023 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-38100544

RESUMEN

Regulatory T (Treg) cells contribute to immune homeostasis but suppress immune responses to cancer. Strategies to disrupt Treg cell-mediated cancer immunosuppression have been met with limited clinical success, but the underlying mechanisms for treatment failure are poorly understood. By modeling Treg cell-targeted immunotherapy in mice, we find that CD4+ Foxp3- conventional T (Tconv) cells acquire suppressive function upon depletion of Foxp3+ Treg cells, limiting therapeutic efficacy. Foxp3- Tconv cells within tumors adopt a Treg cell-like transcriptional profile upon ablation of Treg cells and acquire the ability to suppress T cell activation and proliferation ex vivo. Suppressive activity is enriched among CD4+ Tconv cells marked by expression of C-C motif receptor 8 (CCR8), which are found in mouse and human tumors. Upon Treg cell depletion, CCR8+ Tconv cells undergo systemic and intratumoral activation and expansion, and mediate IL-10-dependent suppression of antitumor immunity. Consequently, conditional deletion of Il10 within T cells augments antitumor immunity upon Treg cell depletion in mice, and antibody blockade of IL-10 signaling synergizes with Treg cell depletion to overcome treatment resistance. These findings reveal a secondary layer of immunosuppression by Tconv cells released upon therapeutic Treg cell depletion and suggest that broader consideration of suppressive function within the T cell lineage is required for development of effective Treg cell-targeted therapies.


Asunto(s)
Neoplasias , Linfocitos T Reguladores , Ratones , Humanos , Animales , Interleucina-10/metabolismo , Neoplasias/terapia , Neoplasias/metabolismo , Inmunoterapia , Factores de Transcripción Forkhead/metabolismo
2.
J Exp Med ; 219(12)2022 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-36178457

RESUMEN

Natural killer (NK) cells are critical to immune surveillance against infections and cancer. Their role in immune surveillance requires that NK cells are present within tissues in a quiescent state. Mechanisms by which NK cells remain quiescent in tissues are incompletely elucidated. The transcriptional repressor BACH2 plays a critical role within the adaptive immune system, but its function within innate lymphocytes has been unclear. Here, we show that BACH2 acts as an intrinsic negative regulator of NK cell maturation and function. BACH2 is expressed within developing and mature NK cells and promotes the maintenance of immature NK cells by restricting their maturation in the presence of weak stimulatory signals. Loss of BACH2 within NK cells results in accumulation of activated NK cells with unrestrained cytotoxic function within tissues, which mediate augmented immune surveillance to pulmonary cancer metastasis. These findings establish a critical function of BACH2 as a global negative regulator of innate cytotoxic function and tumor immune surveillance by NK cells.


Asunto(s)
Antineoplásicos , Neoplasias , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Humanos , Inmunidad Innata , Células Asesinas Naturales
3.
Immunology ; 163(4): 512-520, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33838058

RESUMEN

CD4+ regulatory T (Treg) cells, dependent upon the transcription factor Foxp3, contribute to tumour immunosuppression but are also required for immune homeostasis. There is interest in developing therapies that selectively target the immunosuppressive function of Treg cells within tumours without disrupting their systemic anti-inflammatory function. High levels of expression of chemokine (C-C motif) receptor 8 (CCR8) discriminate Treg cells within tumours from those found in systemic lymphoid tissues. It has recently been proposed that disruption of CCR8 function using blocking anti-CCR8 antibodies results in reduced accumulation of Treg cells within tumours and disruption of their immunosuppressive function. Here, using Ccr8-/- mice, we show that CCR8 function is not required for Treg cell accumulation or immunosuppression in the context of syngeneic MC38 colorectal adenocarcinoma and B16 melanoma tumours. We observed high levels of CCR8 expression on tumour-infiltrating Treg cells which were abolished in Ccr8-/- mice. High levels of CCR8 marked cells with high levels of suppressive function. However, whereas systemic ablation of Treg cells resulted in strikingly diminished tumour burden, growth of subcutaneously implanted tumours was unaffected by systemic CCR8 loss. Consistently, we observed minimal impact of systemic CCR8 ablation on the frequency, phenotype and function of tumour-infiltrating Treg cells and conventional T (Tconv) function. These findings suggest that CCR8 is not required for Treg cell accumulation and immunosuppressive function within tumours and that depletion of CCR8+ Treg cells rather than blockade of CCR8 function is a more promising avenue for selective immunotherapy.


Asunto(s)
Adenocarcinoma/inmunología , Neoplasias Colorrectales/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/inmunología , Receptores CCR8/metabolismo , Neoplasias Cutáneas/inmunología , Linfocitos T Reguladores/inmunología , Animales , Factores de Transcripción Forkhead/metabolismo , Humanos , Tolerancia Inmunológica , Melanoma Experimental , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores CCR8/genética
4.
Nature ; 583(7816): 447-452, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32499651

RESUMEN

Genetic variations underlying susceptibility to complex autoimmune and allergic diseases are concentrated within noncoding regulatory elements termed enhancers1. The functions of a large majority of disease-associated enhancers are unknown, in part owing to their distance from the genes they regulate, a lack of understanding of the cell types in which they operate, and our inability to recapitulate the biology of immune diseases in vitro. Here, using shared synteny to guide loss-of-function analysis of homologues of human enhancers in mice, we show that the prominent autoimmune and allergic disease risk locus at chromosome 11q13.52-7 contains a distal enhancer that is functional in CD4+ regulatory T (Treg) cells and required for Treg-mediated suppression of colitis. The enhancer recruits the transcription factors STAT5 and NF-κB to mediate signal-driven expression of Lrrc32, which encodes the protein glycoprotein A repetitions predominant (GARP). Whereas disruption of the Lrrc32 gene results in early lethality, mice lacking the enhancer are viable but lack GARP expression in Foxp3+ Treg cells, which are unable to control colitis in a cell-transfer model of the disease. In human Treg cells, the enhancer forms conformational interactions with the promoter of LRRC32 and enhancer risk variants are associated with reduced histone acetylation and GARP expression. Finally, functional fine-mapping of 11q13.5 using CRISPR-activation (CRISPRa) identifies a CRISPRa-responsive element in the vicinity of risk variant rs11236797 capable of driving GARP expression. These findings provide a mechanistic basis for association of the 11q13.5 risk locus with immune-mediated diseases and identify GARP as a potential target in their therapy.


Asunto(s)
Cromosomas Humanos Par 11/genética , Colitis/genética , Colitis/inmunología , Elementos de Facilitación Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Linfocitos T Reguladores/inmunología , Acetilación , Alelos , Animales , Cromosomas de los Mamíferos/genética , Femenino , Factores de Transcripción Forkhead/metabolismo , Histonas/metabolismo , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Sintenía/genética
5.
J Exp Med ; 217(9)2020 09 07.
Artículo en Inglés | MEDLINE | ID: mdl-32515782

RESUMEN

Regulatory T (Treg) cell populations are composed of functionally quiescent resting Treg (rTreg) cells which differentiate into activated Treg (aTreg) cells upon antigen stimulation. How rTreg cells remain quiescent despite chronic exposure to cognate self- and foreign antigens is unclear. The transcription factor BACH2 is critical for early Treg lineage specification, but its function following lineage commitment is unresolved. Here, we show that BACH2 is repurposed following Treg lineage commitment and promotes the quiescence and long-term maintenance of rTreg cells. Bach2 is highly expressed in rTreg cells but is down-regulated in aTreg cells and during inflammation. In rTreg cells, BACH2 binds to enhancers of genes involved in aTreg differentiation and represses their TCR-driven induction by competing with AP-1 factors for DNA binding. This function promotes rTreg cell quiescence and long-term maintenance and is required for immune homeostasis and durable immunosuppression in cancer. Thus, BACH2 supports a "division of labor" between quiescent rTreg cells and their activated progeny in Treg maintenance and function, respectively.


Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Ciclo Celular , Homeostasis , Terapia de Inmunosupresión , Neoplasias/inmunología , Neoplasias/patología , Linfocitos T Reguladores/inmunología , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/deficiencia , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Línea Celular Tumoral , Linaje de la Célula , Citocinas/metabolismo , Regulación hacia Abajo , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Inflamación/patología , Integrasas/metabolismo , Ratones Endogámicos C57BL , Neoplasias/genética , Fenotipo , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T Reguladores/citología , Factor de Transcripción AP-1/metabolismo
6.
JCI Insight ; 3(11)2018 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-29875321

RESUMEN

Redundancy and compensation provide robustness to biological systems but may contribute to therapy resistance. Both tumor-associated macrophages (TAMs) and Foxp3+ regulatory T (Treg) cells promote tumor progression by limiting antitumor immunity. Here we show that genetic ablation of CSF1 in colorectal cancer cells reduces the influx of immunosuppressive CSF1R+ TAMs within tumors. This reduction in CSF1-dependent TAMs resulted in increased CD8+ T cell attack on tumors, but its effect on tumor growth was limited by a compensatory increase in Foxp3+ Treg cells. Similarly, disruption of Treg cell activity through their experimental ablation produced moderate effects on tumor growth and was associated with elevated numbers of CSF1R+ TAMs. Importantly, codepletion of CSF1R+ TAMs and Foxp3+ Treg cells resulted in an increased influx of CD8+ T cells, augmentation of their function, and a synergistic reduction in tumor growth. Further, inhibition of Treg cell activity either through systemic pharmacological blockade of PI3Kδ, or its genetic inactivation within Foxp3+ Treg cells, sensitized previously unresponsive solid tumors to CSF1R+ TAM depletion and enhanced the effect of CSF1R blockade. These findings identify CSF1R+ TAMs and PI3Kδ-driven Foxp3+ Treg cells as the dominant compensatory cellular components of the immunosuppressive tumor microenvironment, with implications for the design of combinatorial immunotherapies.


Asunto(s)
Resistencia a Antineoplásicos/inmunología , Depleción Linfocítica/métodos , Macrófagos/inmunología , Neoplasias/tratamiento farmacológico , Linfocitos T Reguladores/inmunología , Aminopiridinas/administración & dosificación , Animales , Línea Celular Tumoral/trasplante , Fosfatidilinositol 3-Quinasa Clase I , Toxina Diftérica/administración & dosificación , Modelos Animales de Enfermedad , Femenino , Factores de Transcripción Forkhead/metabolismo , Técnicas de Inactivación de Genes , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Transgénicos , Neoplasias/inmunología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Cultivo Primario de Células , Purinas/administración & dosificación , Pirroles/administración & dosificación , Quinazolinonas/administración & dosificación , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismo , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología
7.
J Clin Invest ; 126(2): 599-604, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26731475

RESUMEN

The immune system has a powerful ability to recognize and kill cancer cells, but its function is often suppressed within tumors, preventing clearance of disease. Functionally diverse innate and adaptive cellular lineages either drive or constrain immune reactions within tumors. The transcription factor (TF) BACH2 regulates the differentiation of multiple innate and adaptive cellular lineages, but its role in controlling tumor immunity has not been elucidated. Here, we demonstrate that BACH2 is required to establish immunosuppression within tumors. Tumor growth was markedly impaired in Bach2-deficient mice and coincided with intratumoral activation of both innate and adaptive immunity. However, augmented tumor clearance in the absence of Bach2 was dependent upon the adaptive immune system. Analysis of tumor-infiltrating lymphocytes from Bach2-deficient mice revealed high frequencies of rapidly proliferating effector CD4+ and CD8+ T cells that expressed the inflammatory cytokine IFN-γ. Effector T cell activation coincided with a reduction in the frequency of intratumoral Foxp3+ Tregs. Mechanistically, BACH2 promoted tumor immunosuppression through Treg-mediated inhibition of intratumoral CD8+ T cells and IFN-γ. These findings demonstrate that BACH2 is a key component of the molecular program of tumor immunosuppression and identify therapeutic targets for the reversal of immunosuppression in cancer.


Asunto(s)
Inmunidad Adaptativa , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunidad Innata , Neoplasias/inmunología , Linfocitos T Reguladores/inmunología , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Linfocitos T CD8-positivos/patología , Interferón gamma/genética , Interferón gamma/inmunología , Ratones , Ratones Noqueados , Neoplasias/genética , Neoplasias/patología , Linfocitos T Reguladores/patología
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