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1.
Annu Rev Immunol ; 42(1): 647-677, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38424658

RESUMO

Lymphocytes spanning the entire innate-adaptive spectrum can stably reside in tissues and constitute an integral component of the local defense network against immunological challenges. In tight interactions with the epithelium and endothelium, tissue-resident lymphocytes sense antigens and alarmins elicited by infectious microbes and abiotic stresses at barrier sites and mount effector responses to restore tissue homeostasis. Of note, such a host cell-directed immune defense system has been recently demonstrated to surveil epithelial cell transformation and carcinoma development, as well as cancer cell metastasis at selected distant organs, and thus represents a primordial cancer immune defense module. Here we review how distinct lineages of tissue-resident innate lymphoid cells, innate-like T cells, and adaptive T cells participate in a form of multilayered cancer immunity in murine models and patients, and how their convergent effector programs may be targeted through both shared and private regulatory pathways for cancer immunotherapy.


Assuntos
Imunidade Inata , Neoplasias , Humanos , Animais , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos/imunologia , Linfócitos/metabolismo , Microambiente Tumoral/imunologia , Imunidade Adaptativa , Imunoterapia/métodos
2.
Nat Immunol ; 24(8): 1358-1369, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37365386

RESUMO

Following infection or vaccination, activated B cells at extrafollicular sites or within germinal centers (GCs) undergo vigorous clonal proliferation. Proliferating lymphocytes have been shown to undertake lactate dehydrogenase A (LDHA)-dependent aerobic glycolysis; however, the specific role of this metabolic pathway in a B cell transitioning from a naïve to a highly proliferative, activated state remains poorly defined. Here, we deleted LDHA in a stage-specific and cell-specific manner. We find that ablation of LDHA in a naïve B cell did not profoundly affect its ability to undergo a bacterial lipopolysaccharide-induced extrafollicular B cell response. On the other hand, LDHA-deleted naïve B cells had a severe defect in their capacities to form GCs and mount GC-dependent antibody responses. In addition, loss of LDHA in T cells severely compromised B cell-dependent immune responses. Strikingly, when LDHA was deleted in activated, as opposed to naïve, B cells, there were only minimal effects on the GC reaction and in the generation of high-affinity antibodies. These findings strongly suggest that naïve and activated B cells have distinct metabolic requirements that are further regulated by niche and cellular interactions.


Assuntos
Linfócitos B , Centro Germinativo , Linfócitos T , Ativação Linfocitária , Comunicação Celular
3.
Nat Immunol ; 23(6): 904-915, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35618834

RESUMO

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.


Assuntos
Neoplasias da Mama , Interleucina-15/metabolismo , Animais , Neoplasias da Mama/genética , Linfócitos T CD8-Positivos , Feminino , Granzimas , Humanos , Imunidade Inata , Linfócitos , Camundongos
4.
Immunity ; 56(1): 14-31, 2023 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-36630912

RESUMO

Metazoan tissue specification is associated with integration of macrophage lineage cells in sub-tissular niches to promote tissue development and homeostasis. Oncogenic transformation, most prevalently of epithelial cell lineages, results in maladaptation of resident tissue macrophage differentiation pathways to generate parenchymal and interstitial tumor-associated macrophages that largely foster cancer progression. In addition to growth factors, nutrients that can be consumed, stored, recycled, or converted to signaling molecules have emerged as crucial regulators of macrophage responses in tumor. Here, we review how nutrient acquisition through plasma membrane transporters and engulfment pathways control tumor-associated macrophage differentiation and function. We also discuss how nutrient metabolism regulates tumor-associated macrophages and how these processes may be targeted for cancer therapy.


Assuntos
Neoplasias , Macrófagos Associados a Tumor , Animais , Humanos , Macrófagos Associados a Tumor/metabolismo , Macrófagos/metabolismo , Diferenciação Celular , Neoplasias/metabolismo , Nutrientes
5.
Immunity ; 56(11): 2555-2569.e5, 2023 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-37967531

RESUMO

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.


Assuntos
Células Progenitoras Endoteliais , Proteínas Supressoras de Tumor , Animais , Humanos , Serina-Treonina Quinases TOR/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa/genética , Macrófagos Associados a Tumor/metabolismo , Células Progenitoras Endoteliais/metabolismo , Receptor de Proteína C Endotelial , Alvo Mecanístico do Complexo 1 de Rapamicina , Neovascularização Patológica , Mamíferos
6.
Nat Immunol ; 20(9): 1208-1219, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31384057

RESUMO

Regulatory T cells (Treg cells) deficient in the transcription factor Foxp3 lack suppressor function and manifest an effector T (Teff) cell-like phenotype. We demonstrate that Foxp3 deficiency dysregulates metabolic checkpoint kinase mammalian target of rapamycin (mTOR) complex 2 (mTORC2) signaling and gives rise to augmented aerobic glycolysis and oxidative phosphorylation. Specific deletion of the mTORC2 adaptor gene Rictor in Foxp3-deficient Treg cells ameliorated disease in a Foxo1 transcription factor-dependent manner. Rictor deficiency re-established a subset of Treg cell genetic circuits and suppressed the Teff cell-like glycolytic and respiratory programs, which contributed to immune dysregulation. Treatment of Treg cells from patients with FOXP3 deficiency with mTOR inhibitors similarly antagonized their Teff cell-like program and restored suppressive function. Thus, regulatory function can be re-established in Foxp3-deficient Treg cells by targeting their metabolic pathways, providing opportunities to restore tolerance in Treg cell disorders.


Assuntos
Reprogramação Celular/imunologia , Fatores de Transcrição Forkhead/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Proteína Companheira de mTOR Insensível à Rapamicina/genética , Linfócitos T Reguladores/imunologia , Animais , Células Cultivadas , Feminino , Regulação da Expressão Gênica , Glicólise/fisiologia , Humanos , Masculino , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação Oxidativa , Transdução de Sinais , Linfócitos T Reguladores/citologia
7.
Immunity ; 55(11): 2044-2058.e5, 2022 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-36288724

RESUMO

Tumors are populated by antigen-presenting cells (APCs) including macrophage subsets with distinct origins and functions. Here, we examined how cancer impacts mononuclear phagocytic APCs in a murine model of breast cancer. Tumors induced the expansion of monocyte-derived tumor-associated macrophages (TAMs) and the activation of type 1 dendritic cells (DC1s), both of which expressed and required the transcription factor interferon regulatory factor-8 (IRF8). Although DC1s mediated cytotoxic T lymphocyte (CTL) priming in tumor-draining lymph nodes, TAMs promoted CTL exhaustion in the tumor, and IRF8 was required for TAMs' ability to present cancer cell antigens. TAM-specific IRF8 deletion prevented exhaustion of cancer-cell-reactive CTLs and suppressed tumor growth. Tumors from patients with immune-infiltrated renal cell carcinoma had abundant TAMs that expressed IRF8 and were enriched for an IRF8 gene expression signature. Furthermore, the TAM-IRF8 signature co-segregated with CTL exhaustion signatures across multiple cancer types. Thus, CTL exhaustion is promoted by TAMs via IRF8.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Animais , Camundongos , Macrófagos Associados a Tumor , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Linfócitos T Citotóxicos , Células Dendríticas
8.
Cell ; 164(3): 365-77, 2016 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-26806130

RESUMO

Malignancy can be suppressed by the immune system in a process termed immunosurveillance. However, to what extent immunosurveillance occurs in spontaneous cancers and the composition of participating cell types remains obscure. Here, we show that cell transformation triggers a tissue-resident lymphocyte response in oncogene-induced murine cancer models. Non-circulating cytotoxic lymphocytes, derived from innate, T cell receptor (TCR)αß, and TCRγδ lineages, expand in early tumors. Characterized by high expression of NK1.1, CD49a, and CD103, these cells share a gene-expression signature distinct from those of conventional NK cells, T cells, and invariant NKT cells. Generation of these lymphocytes is dependent on the cytokine IL-15, but not the transcription factor Nfil3 that is required for the differentiation of tumor-infiltrating NK cells, and IL-15 deficiency, but not Nfil3 deficiency, results in accelerated tumor growth. These findings reveal a tumor-elicited immunosurveillance mechanism that engages unconventional type-1-like innate lymphoid cells and type 1 innate-like T cells.


Assuntos
Linfócitos/imunologia , Neoplasias Mamárias Experimentais/imunologia , Monitorização Imunológica , Subpopulações de Linfócitos T/imunologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Granzimas/metabolismo , Interleucina-15/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo
9.
Nat Immunol ; 19(9): 986-1000, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30127432

RESUMO

Gain-of-function mutations in the gene encoding the phosphatidylinositol-3-OH kinase catalytic subunit p110δ (PI3Kδ) result in a human primary immunodeficiency characterized by lymphoproliferation, respiratory infections and inefficient responses to vaccines. However, what promotes these immunological disturbances at the cellular and molecular level remains unknown. We generated a mouse model that recapitulated major features of this disease and used this model and patient samples to probe how hyperactive PI3Kδ fosters aberrant humoral immunity. We found that mutant PI3Kδ led to co-stimulatory receptor ICOS-independent increases in the abundance of follicular helper T cells (TFH cells) and germinal-center (GC) B cells, disorganized GCs and poor class-switched antigen-specific responses to immunization, associated with altered regulation of the transcription factor FOXO1 and pro-apoptotic and anti-apoptotic members of the BCL-2 family. Notably, aberrant responses were accompanied by increased reactivity to gut bacteria and a broad increase in autoantibodies that were dependent on stimulation by commensal microbes. Our findings suggest that proper regulation of PI3Kδ is critical for ensuring optimal host-protective humoral immunity despite tonic stimulation from the commensal microbiome.


Assuntos
Linfócitos B/fisiologia , Microbioma Gastrointestinal/imunologia , Centro Germinativo/fisiologia , Mutação/genética , Fosfatidilinositol 3-Quinases/genética , Linfócitos T Auxiliares-Indutores/fisiologia , Animais , Autoanticorpos/sangue , Células Cultivadas , Classe I de Fosfatidilinositol 3-Quinases/genética , Modelos Animais de Doenças , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Humanos , Imunidade Humoral/genética , Switching de Imunoglobulina/genética , Síndromes de Imunodeficiência/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
10.
Immunity ; 54(5): 976-987.e7, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33979589

RESUMO

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.


Assuntos
Trifosfato de Adenosina/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Transdução de Sinais/fisiologia , Células Th17/metabolismo , Animais , Diferenciação Celular/fisiologia , Linhagem Celular , Proliferação de Células/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Glucose/metabolismo , Doença de Depósito de Glicogênio/metabolismo , Glicólise/fisiologia , L-Lactato Desidrogenase/deficiência , L-Lactato Desidrogenase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
12.
Cell ; 159(1): 122-133, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25259925

RESUMO

Mechanistic target of rapamycin complex 1 (mTORC1) integrates diverse environmental signals to control cellular growth and organismal homeostasis. In response to nutrients, Rag GTPases recruit mTORC1 to the lysosome to be activated, but how Rags are regulated remains incompletely understood. Here, we show that Sestrins bind to the heterodimeric RagA/B-RagC/D GTPases, and function as guanine nucleotide dissociation inhibitors (GDIs) for RagA/B. Sestrin overexpression inhibits amino-acid-induced Rag guanine nucleotide exchange and mTORC1 translocation to the lysosome. Mutation of the conserved GDI motif creates a dominant-negative form of Sestrin that renders mTORC1 activation insensitive to amino acid deprivation, whereas a cell-permeable peptide containing the GDI motif inhibits mTORC1 signaling. Mice deficient in all Sestrins exhibit reduced postnatal survival associated with defective mTORC1 inactivation in multiple organs during neonatal fasting. These findings reveal a nonredundant mechanism by which the Sestrin family of GDIs regulates the nutrient-sensing Rag GTPases to control mTORC1 signaling.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas de Choque Térmico/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas Nucleares/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Sequência de Aminoácidos , Aminoácidos/metabolismo , Animais , Animais Recém-Nascidos , Proteínas de Ciclo Celular/genética , Embrião de Mamíferos/citologia , Feminino , Fibroblastos/metabolismo , Técnicas de Introdução de Genes , Proteínas de Choque Térmico/genética , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Proteínas Monoméricas de Ligação ao GTP/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Proteínas Nucleares/genética , Peroxidases , Gravidez , Alinhamento de Sequência , Inanição/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/metabolismo
13.
Nature ; 619(7970): 616-623, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37380769

RESUMO

In metazoan organisms, cell competition acts as a quality control mechanism to eliminate unfit cells in favour of their more robust neighbours1,2. This mechanism has the potential to be maladapted, promoting the selection of aggressive cancer cells3-6. Tumours are metabolically active and are populated by stroma cells7,8, but how environmental factors affect cancer cell competition remains largely unknown. Here we show that tumour-associated macrophages (TAMs) can be dietarily or genetically reprogrammed to outcompete MYC-overexpressing cancer cells. In a mouse model of breast cancer, MYC overexpression resulted in an mTORC1-dependent 'winner' cancer cell state. A low-protein diet inhibited mTORC1 signalling in cancer cells and reduced tumour growth, owing unexpectedly to activation of the transcription factors TFEB and TFE3 and mTORC1 in TAMs. Diet-derived cytosolic amino acids are sensed by Rag GTPases through the GTPase-activating proteins GATOR1 and FLCN to control Rag GTPase effectors including TFEB and TFE39-14. Depletion of GATOR1 in TAMs suppressed the activation of TFEB, TFE3 and mTORC1 under the low-protein diet condition, causing accelerated tumour growth; conversely, depletion of FLCN or Rag GTPases in TAMs activated TFEB, TFE3 and mTORC1 under the normal protein diet condition, causing decelerated tumour growth. Furthermore, mTORC1 hyperactivation in TAMs and cancer cells and their competitive fitness were dependent on the endolysosomal engulfment regulator PIKfyve. Thus, noncanonical engulfment-mediated Rag GTPase-independent mTORC1 signalling in TAMs controls competition between TAMs and cancer cells, which defines a novel innate immune tumour suppression pathway that could be targeted for cancer therapy.


Assuntos
Competição entre as Células , Técnicas de Reprogramação Celular , Imunidade Inata , Neoplasias , Macrófagos Associados a Tumor , Animais , Camundongos , Aminoácidos/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Competição entre as Células/genética , Competição entre as Células/imunologia , Proteínas Alimentares/farmacologia , Modelos Animais de Doenças , GTP Fosfo-Hidrolases/metabolismo , Lisossomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo
14.
Immunity ; 51(3): 479-490.e6, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31402259

RESUMO

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.


Assuntos
Homeostase/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , MicroRNAs/imunologia , Animais , Linhagem Celular , Feminino , Células HEK293 , Humanos , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Muromegalovirus/imunologia , Células NIH 3T3 , Receptores de Interleucina-15/imunologia , Transdução de Sinais/imunologia , Proteínas Supressoras da Sinalização de Citocina/imunologia , Fator de Crescimento Transformador beta/imunologia
15.
Nature ; 605(7908): 139-145, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35444279

RESUMO

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.


Assuntos
Imunidade Inata , Interleucina-15 , Neoplasias , Animais , Diferenciação Celular , Camundongos , Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T Citotóxicos/metabolismo
16.
Immunol Rev ; 323(1): 150-163, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38506480

RESUMO

Cancer progression can be restrained by tumor-infiltrating lymphocytes in a process termed cancer immunosurveillance. Based on how lymphocytes are activated and recruited to the tumor tissue, cancer immunity is either pre-wired, in which innate lymphocytes and innate-like T cells are directly recruited to and activated in tumors following their differentiation in primary lymphoid organs; or priming-dependent, in which conventional adaptive T cells are first primed by cognate antigens in secondary lymphoid organs before homing to and reactivated in tumors. While priming-dependent cancer immunity has been a focus of cancer immunology research for decades, in part due to historical preconception of cancer theory and tumor model choice as well as clinical success of conventional adaptive T cell-directed therapeutic programs, recent studies have revealed that pre-wired cancer immunity mediated by tissue-resident type 1 innate lymphoid cells (ILC1s) and killer innate-like T cells (ILTCKs) is an integral component of the cancer immunosurveillance process. Herein we review the distinct ontogenies and cancer-sensing mechanisms of ILC1s and ILTCKs in murine genetic cancer models as well as the conspicuously conserved responses in human malignancies. How ILC1s and ILTCKs may be targeted to broaden the scope of cancer immunotherapy beyond conventional adaptive T cells is also discussed.


Assuntos
Imunidade Inata , Neoplasias , Humanos , Animais , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Células Matadoras Naturais/imunologia , Vigilância Imunológica , Microambiente Tumoral/imunologia , Camundongos , Linfócitos/imunologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
17.
Cell ; 151(1): 153-66, 2012 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-23021222

RESUMO

Regulatory T (Treg) cells, whose identity and function are defined by the transcription factor Foxp3, are indispensable for immune homeostasis. It is unclear whether Foxp3 exerts its Treg lineage specification function through active modification of the chromatin landscape and establishment of new enhancers or by exploiting a pre-existing enhancer landscape. Analysis of the chromatin accessibility of Foxp3-bound enhancers in Treg and Foxp3-negative T cells showed that Foxp3 was bound overwhelmingly to preaccessible enhancers occupied by its cofactors in precursor cells or a structurally related predecessor. Furthermore, the bulk of Foxp3-bound Treg cell enhancers lacking in Foxp3(-) CD4(+) cells became accessible upon T cell receptor activation prior to Foxp3 expression, and only a small subset associated with several functionally important genes were exclusively Treg cell specific. Thus, in a late cellular differentiation process, Foxp3 defines Treg cell functionality in an "opportunistic" manner by largely exploiting the preformed enhancer network instead of establishing a new enhancer landscape.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Linfócitos T Reguladores/citologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular , Cromatina/metabolismo , Elementos Facilitadores Genéticos , Feminino , Proteína Forkhead Box O1 , Ativação Linfocitária , Camundongos , Organismos Livres de Patógenos Específicos , Linfócitos T Reguladores/metabolismo
18.
Immunity ; 46(1): 3-5, 2017 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-28099863

RESUMO

Mechanisms that govern PD1 expression and exhaustion in T cells are not fully understood. In this issue of Immunity, Stephen et al. (2017) uncover a key role for the genome organizer Satb1 in restraining PD1 expression and promoting tumor immunity.


Assuntos
Proteínas de Ligação à Região de Interação com a Matriz/genética , Linfócitos T , Genoma , Humanos
19.
Nature ; 587(7832): 121-125, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33087933

RESUMO

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.


Assuntos
Neoplasias da Mama/terapia , Imunoterapia , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Hipóxia Celular , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Interleucina-4/imunologia , Linfonodos/citologia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Masculino , Camundongos , Receptor do Fator de Crescimento Transformador beta Tipo II/química , Receptor do Fator de Crescimento Transformador beta Tipo II/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Fator de Crescimento Transformador beta/imunologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
Nature ; 587(7832): 115-120, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33087928

RESUMO

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.


Assuntos
Neoplasias/imunologia , Neoplasias/patologia , Transdução de Sinais/imunologia , Células Th2/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Morte Celular/efeitos dos fármacos , Hipóxia Celular , Linhagem Celular , Progressão da Doença , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Interferon gama/imunologia , Interleucina-4/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/irrigação sanguínea , Neoplasias/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II/deficiência , Transdução de Sinais/efeitos dos fármacos , Células Estromais/citologia , Células Estromais/imunologia , Células Th2/metabolismo , Fator de Crescimento Transformador beta/antagonistas & inibidores
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