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1.
Cancer Immunol Res ; 7(9): 1426-1439, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31308016

RESUMO

The adoptive transfer of ex vivo-expanded T cells is a promising approach to treat several malignancies. Several lines of evidence support that the infusion of T cells with early memory features, capable of expanding and persisting after transfer, are associated with better outcomes. We report herein that exposure to exogenous TGFß during human T-cell stimulation ex vivo leads to the accumulation of early/central memory (Tcm) cells. Exposure to TGFß suppressed the expression of BLIMP-1, a key orchestrator of effector T-cell differentiation, and led to the upregulation of the memory-associated transcription factor ID3. Accordingly, this was associated with an early memory transcriptional signature in both CD4+ and CD8+ T-cell subsets. The T cells stimulated in the presence of TGFß expanded normally, and displayed polyfunctional features and no suppressive activity. The adoptive transfer of ex vivo-stimulated T cells into immunodeficient mice confirmed that TGFß-conditioned cells had an enhanced capacity to persist and mediate xenogeneic graft-versus-host disease, as predicted by their early T-cell memory phenotype. Chimeric antigen receptor-expressing T cells generated in the presence of exogenous TGFß were cytotoxic and more effective at controlling tumor growth in immunodeficient animals. This work unveils a new role for TGFß in memory T-cell differentiation and indicates that TGFß signaling may be harnessed to program Tcm differentiation in the context of ex vivo T-cell stimulation for adoptive immunotherapy in humans.


Assuntos
Diferenciação Celular/imunologia , Memória Imunológica , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Apoptose/imunologia , Biomarcadores , Proliferação de Células , Células Cultivadas , Citocinas/metabolismo , Metilação de DNA , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/metabolismo , Humanos , Memória Imunológica/efeitos dos fármacos , Memória Imunológica/genética , Imunomodulação , Imunofenotipagem , Imunoterapia Adotiva/métodos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Subpopulações de Linfócitos T/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Cancers (Basel) ; 10(6)2018 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-29891791

RESUMO

Transforming Growth Factor beta (TGF-β) is a pleiotropic cytokine produced in large amounts within cancer microenvironments that will ultimately promote neoplastic progression, notably by suppressing the host’s T-cell immunosurveillance. This effect is mostly due to the well-known inhibitory effect of TGF-β on T cell proliferation, activation, and effector functions. Moreover, TGF-β subverts T cell immunity by favoring regulatory T-cell differentiation, further reinforcing immunosuppression within tumor microenvironments. These findings stimulated the development of many strategies to block TGF-β or its signaling pathways, either as monotherapy or in combination with other therapies, to restore anti-cancer immunity. Paradoxically, recent studies provided evidence that TGF-β can also promote differentiation of certain inflammatory populations of T cells, such as Th17, Th9, and resident-memory T cells (Trm), which have been associated with improved tumor control in several models. Here, we review current advances in our understanding of the many roles of TGF-β in T cell biology in the context of tumor immunity and discuss the possibility to manipulate TGF-β signaling to improve cancer immunotherapy.

3.
Transplantation ; 101(11): 2713-2721, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28230645

RESUMO

BACKGROUND: Polyomavirus-associated nephropathy (PVAN) after BK virus reactivation in kidney transplant recipients (KTR) can compromise graft survival. Lowering immunosuppression is the only established approach to prevent or treat PVAN but nonspecifically increasing host immune competence also augments rejection risk. Ex vivo T cell stimulation/expansion offers the possibility to generate BK-specific T cell lines for adoptive immunotherapy. The objective of this study was to develop and characterize a clinical-scale protocol to generate BK-specific T cell lines from viremic KTR. METHODS: Peripheral blood mononuclear cells from healthy controls and viremic KTR were stimulated using BK virus peptide libraries loaded or not on monocytes-derived dendritic cells. Cell counts, flow cytometry, and next-generation sequencing were used to assess T cell expansion, differentiation, and clonal diversity. Enzyme-linked immunospots, cytotoxicity assays as well as adoptive transfer in NOD/SCID/IL2Rγ mice were used to assess for pathogen-specificity and evidence of nonspecific alloreactivity. RESULTS: T cell lines from KTR and healthy control showed similar characteristics, implying that ongoing immunosuppression and chronic virus exposure do not compromise the differentiation, specificity, or clonal diversity of T cell lines after ex vivo production. Using antigen-loaded dendritic cells improved T cell expansion and favored central memory T cell differentiation. The T cell lines were antigen-specific and showed no nonspecific alloreactivity in vitro and in vivo. CONCLUSIONS: Using a rapid, clinically compliant culture system, we show that autologous BK virus-specific T cell lines can be reliably generated from viremic KTR. Our results pave the way for the treatment or prevention of PVAN with adoptive immunotherapy.


Assuntos
Transferência Adotiva/métodos , Vírus BK/imunologia , Transplante de Rim/efeitos adversos , Infecções por Polyomavirus/terapia , Linfócitos T/transplante , Infecções Tumorais por Vírus/terapia , Animais , Antígenos Virais/imunologia , Estudos de Casos e Controles , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Separação Celular , Técnicas de Cocultura , Células Dendríticas/imunologia , Células Dendríticas/virologia , Humanos , Hospedeiro Imunocomprometido , Memória Imunológica , Imunossupressores/efeitos adversos , Subunidade gama Comum de Receptores de Interleucina/deficiência , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade gama Comum de Receptores de Interleucina/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/virologia , Ativação Linfocitária , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Fenótipo , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/virologia , Linfócitos T/imunologia , Linfócitos T/virologia , Fatores de Tempo , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/virologia , Ativação Viral
4.
J Immunol ; 197(10): 3927-3935, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27815442

RESUMO

To stimulate a productive T cell response, dendritic cells (DC) must undergo maturation characterized by heightened cell surface expression of MHC and costimulatory molecules as well as cytokine production. Conversely, the inhibition of DC maturation is a central mechanism of immune tolerance. The control of the DC maturation process relies on the integration of several cellular stimulatory or inhibitory signals. The soluble factors and their receptors controlling this central aspect of DC biology are incompletely characterized. We show that murine bone marrow-derived DC (BMDC) maturation induced by LPS, as opposed to polyinosinic:polycytidylic acid or cytosine-phosphate-guanine, is robustly inhibited by vascular endothelial growth factor (VEGF), a previously identified immunosuppressive cytokine. Using BMDC from wild type and conditional knockout mice, we show that neuropilin-1 (NRP-1), a known receptor of VEGF, is necessary to suppress LPS-dependent BMDC maturation. The absence of NRP-1 had no ostensible effects on the biology of BMDC in the absence of VEGF. However, NRP-1-deficient BMDC remained completely insensitive to the VEGF-dependent inhibition of BMDC maturation in culture. In the presence of VEGF, NRP-1 directly interacted with the LPS receptor TLR4 and suppressed downstream signaling through ERK and NF-κß, resulting in a sharp inhibition of MHC class II and costimulatory molecules (CD40, CD86) expression as well as proinflammatory cytokine production. Consequently, we identify NRP-1 as a target to optimize DC maturation within environments that are rich in VEGF, such as tumors.


Assuntos
Células Dendríticas/efeitos dos fármacos , Células Dendríticas/fisiologia , Neuropilina-1/imunologia , Neuropilina-1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Antígeno B7-2/efeitos dos fármacos , Antígeno B7-2/genética , Células da Medula Óssea/imunologia , Células da Medula Óssea/fisiologia , Antígenos CD40/efeitos dos fármacos , Antígenos CD40/genética , Diferenciação Celular , Células Cultivadas , Citocinas/biossíntese , Citocinas/efeitos dos fármacos , Citocinas/genética , Células Dendríticas/imunologia , Genes MHC da Classe II/efeitos dos fármacos , Genes MHC da Classe II/genética , Tolerância Imunológica/efeitos dos fármacos , Lipopolissacarídeos/imunologia , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Subunidade p50 de NF-kappa B/fisiologia , Neuropilina-1/deficiência , Poli I-C/farmacologia , Transdução de Sinais/imunologia , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia
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