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1.
J Immunother Cancer ; 11(11)2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37963637

RESUMO

BACKGROUND: The metabolism of tryptophan to kynurenines (KYN) by indoleamine-2,3-dioxygenase or tryptophan-2,3-dioxygenase is a key pathway of constitutive and adaptive tumor immune resistance. The immunosuppressive effects of KYN in the tumor microenvironment are predominantly mediated by the aryl hydrocarbon receptor (AhR), a cytosolic transcription factor that broadly suppresses immune cell function. Inhibition of AhR thus offers an antitumor therapy opportunity via restoration of immune system functions. METHODS: The expression of AhR was evaluated in tissue microarrays of head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). A structure class of inhibitors that block AhR activation by exogenous and endogenous ligands was identified, and further optimized, using a cellular screening cascade. The antagonistic properties of the selected AhR inhibitor candidate BAY 2416964 were determined using transactivation assays. Nuclear translocation, target engagement and the effect of BAY 2416964 on agonist-induced AhR activation were assessed in human and mouse cancer cells. The immunostimulatory properties on gene and cytokine expression were examined in human immune cell subsets. The in vivo efficacy of BAY 2416964 was tested in the syngeneic ovalbumin-expressing B16F10 melanoma model in mice. Coculture of human H1299 NSCLC cells, primary peripheral blood mononuclear cells and fibroblasts mimicking the human stromal-tumor microenvironment was used to assess the effects of AhR inhibition on human immune cells. Furthermore, tumor spheroids cocultured with tumor antigen-specific MART-1 T cells were used to study the antigen-specific cytotoxic T cell responses. The data were analyzed statistically using linear models. RESULTS: AhR expression was observed in tumor cells and tumor-infiltrating immune cells in HNSCC, NSCLC and CRC. BAY 2416964 potently and selectively inhibited AhR activation induced by either exogenous or endogenous AhR ligands. In vitro, BAY 2416964 restored immune cell function in human and mouse cells, and furthermore enhanced antigen-specific cytotoxic T cell responses and killing of tumor spheroids. In vivo, oral application with BAY 2416964 was well tolerated, induced a proinflammatory tumor microenvironment, and demonstrated antitumor efficacy in a syngeneic cancer model in mice. CONCLUSIONS: These findings identify AhR inhibition as a novel therapeutic approach to overcome immune resistance in various types of cancers.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Dioxigenases , Neoplasias de Cabeça e Pescoço , Neoplasias Pulmonares , Humanos , Camundongos , Animais , Triptofano , Receptores de Hidrocarboneto Arílico/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Leucócitos Mononucleares/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Cinurenina/metabolismo , Imunoterapia , Fatores Imunológicos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Microambiente Tumoral
2.
Nat Cancer ; 2(7): 723-740, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-35121943

RESUMO

The dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and demonstrate their strict control by the tumor genotype: in isocitrate dehydrogenase (IDH)-mutant tumors, differentiation of infiltrating myeloid cells is blocked, resulting in an immature phenotype. In late-stage gliomas, monocyte-derived macrophages drive tolerogenic alignment of the microenvironment, thus preventing T cell response. We define the IDH-dependent tumor education of infiltrating macrophages to be causally related to a complex re-orchestration of tryptophan metabolism, resulting in activation of the aryl hydrocarbon receptor. We further show that the altered metabolism of IDH-mutant gliomas maintains this axis in bystander cells and that pharmacological inhibition of tryptophan metabolism can reverse immunosuppression. In conclusion, we provide evidence of a glioma genotype-dependent intratumoral network of resident and recruited myeloid cells and identify tryptophan metabolism as a target for immunotherapy of IDH-mutant tumors.


Assuntos
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/genética , Glioma/genética , Humanos , Imunoterapia , Isocitrato Desidrogenase/genética , Triptofano/uso terapêutico , Microambiente Tumoral/genética
3.
Cancer Immunol Res ; 8(7): 895-911, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32312711

RESUMO

The immunoglobulin-like domain containing receptor 2 (ILDR2), a type I transmembrane protein belonging to the B7 family of immunomodulatory receptors, has been described to induce an immunosuppressive effect on T-cell responses. Besides its expression in several nonlymphoid tissue types, we found that ILDR2 was also expressed in fibroblastic reticular cells (FRC) in the stromal part of the lymph node. These immunoregulatory cells were located in the T-cell zone and were essential for the recruitment of naïve T cells and activated dendritic cells to the lymph nodes. Previously, it has been shown that an ILDR2-Fc fusion protein exhibits immunomodulatory effects in several models of autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and type I diabetes. Herein, we report the generation and characterization of a human/mouse/monkey cross-reactive anti-ILDR2 hIgG2 antibody, BAY 1905254, developed to block the immunosuppressive activity of ILDR2 for cancer immunotherapy. BAY 1905254 was shown to promote T-cell activation in vitro and enhance antigen-specific T-cell proliferation and cytotoxicity in vivo in mice. BAY 1905254 also showed potent efficacy in various syngeneic mouse cancer models, and the efficacy was found to correlate with increasing mutational load in the cancer models used. Additive or even synergistic antitumor effects were observed when BAY 1905254 was administered in combination with anti-PD-L1, an immunogenic cell death-inducing chemotherapeutic, or with tumor antigen immunization. Taken together, our data showed that BAY 1905254 is a potential drug candidate for cancer immunotherapy, supporting its further evaluation.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Imunoglobulina G/farmacologia , Ativação Linfocitária/imunologia , Proteínas de Membrana/imunologia , Neoplasias/tratamento farmacológico , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Tolerância Imunológica , Imunoglobulina G/imunologia , Imunoterapia/métodos , Leucócitos Mononucleares/imunologia , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/imunologia , Neoplasias/metabolismo
4.
Immunity ; 34(3): 409-21, 2011 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-21435588

RESUMO

T helper 17 (Th17) cell development is driven by cytokines including transforming growth factor-ß (TGF-ß), interleukin-6 (IL-6), IL-1, and IL-23. Regulatory T (Treg) cells can provide the TGF-ß in vitro, but their role in vivo remains unclear, particularly because Treg cells inhibit inflammation in many models of Th17 cell-associated autoimmunity. We used mice expressing Diphtheria toxin receptor under control of the Foxp3 promoter to deplete Foxp3(+) Treg cells in adult mice during in vivo Th17 cell priming. Treg cell depletion resulted in a reduced frequency of antigen-specific IL-17 producers in draining lymph nodes and blood, correlating with reduced inflammatory skin responses. In contrast, Treg cells did not promote IL-17 secretion after initial activation stages. Treg cell production of TGF-ß was not required for Th17 cell promotion, and neither was suppression of Th1 cell-associated cytokines. Rather, regulation of IL-2 availability and resultant signaling through CD25 by Treg cells was found to play an important role.


Assuntos
Diferenciação Celular , Fatores de Transcrição Forkhead/imunologia , Interleucina-17/imunologia , Interleucina-2/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Células Cultivadas , Camundongos , Camundongos Transgênicos , Modelos Imunológicos
5.
Immunity ; 34(3): 396-408, 2011 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-21435587

RESUMO

TGF-ß1 is a regulatory cytokine that has an important role in controlling T cell differentiation. T cell-produced TGF-ß1 acts on T cells to promote Th17 cell differentiation and the development of experimental autoimmune encephalomyelitis (EAE). However, the exact TGF-ß1-producing T cell subset required for Th17 cell generation and its cellular mechanism of action remain unknown. Here we showed that deletion of the Tgfb1 gene from activated T cells and Treg cells, but not Treg cells alone, abrogated Th17 cell differentiation, resulting in almost complete protection from EAE. Furthermore, differentiation of T cells both in vitro and in vivo demonstrated that TGF-ß1 was highly expressed by Th17 cells and acted in a predominantly autocrine manner to maintain Th17 cells in vivo. These findings reveal an essential role for activated T cell-produced TGF-ß1 in promoting the differentiation of Th17 cells and controlling inflammatory diseases.


Assuntos
Diferenciação Celular , Células Th17/citologia , Células Th17/imunologia , Fator de Crescimento Transformador beta1/imunologia , Animais , Comunicação Autócrina , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase
6.
Immunity ; 28(5): 675-86, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18424188

RESUMO

The action of type I interferons in the central nervous system (CNS) during autoimmunity is largely unknown. Here, we demonstrate elevated interferon beta concentrations in the CNS, but not blood, of mice with experimental autoimmune encephalomyelitis (EAE), a model for CNS autoimmunity. Furthermore, mice devoid of the broadly expressed type I IFN receptor (IFNAR) developed exacerbated clinical disease accompanied by a markedly higher inflammation, demyelination, and lethality without shifting the T helper 17 (Th17) or Th1 cell immune response. Whereas adoptive transfer of encephalitogenic T cells led to enhanced disease in Ifnar1(-/-) mice, newly created conditional mice with B or T lymphocyte-specific IFNAR ablation showed normal EAE. The engagement of IFNAR on neuroectodermal CNS cells had no protective effect. In contrast, absence of IFNAR on myeloid cells led to severe disease with an enhanced effector phase and increased lethality, indicating a distinct protective function of type I IFNs during autoimmune inflammation of the CNS.


Assuntos
Autoimunidade , Sistema Nervoso Central/imunologia , Encefalomielite Autoimune Experimental/imunologia , Interferon beta/metabolismo , Células Mieloides/imunologia , Receptor de Interferon alfa e beta/metabolismo , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Linfócitos B/imunologia , Encéfalo/imunologia , Encéfalo/metabolismo , Sistema Nervoso Central/metabolismo , Progressão da Doença , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Antígenos de Histocompatibilidade Classe II/metabolismo , Interferon beta/imunologia , Camundongos , Camundongos Mutantes , Microglia/metabolismo , Células Mieloides/metabolismo , Receptor de Interferon alfa e beta/imunologia , Transdução de Sinais , Medula Espinal/imunologia , Medula Espinal/metabolismo , Subpopulações de Linfócitos T/metabolismo , Transcrição Gênica
7.
Cell Physiol Biochem ; 20(6): 791-800, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17982261

RESUMO

In this study, we analysed the inhibitory potency, blocking characteristics and putative binding sites of three structurally distinct Kv1.5 channel inhibitors on cloned human Kv1.5 channels. Obtained IC(50) values for S9947, MSD-D and ICAGEN-4 were 0.7 microM, 0.5 microM, and 1.6 microM, respectively. The Hill-coefficients were close to 1 for S9947 and approximately 2 for MSD-D and ICAGEN-4. All three compounds inhibited Kv1.5 channels preferentially in the open state, with Kv1.5 block displaying positive frequency dependence, but no clear voltage and potassium dependence. In contrast to slow on- and off-rates of apparent binding of MSD-D and ICAGEN-4, S9947 had fast on- and off-rates resulting in faster adaptation to changes in pulse frequency. Utilizing Alanine-scanning and in silico modeling we suggest binding of the compounds to the central cavity with crucial residues Ile508 and Val512 in the S6-segment. Residue Thr480 located at the base of the selectivity filter is important for ICAGEN-4 and S9947 inhibition, but less so for MSD-D binding. Our docking models suggest that the innermost potassium ion in the selectivity filter may form a tertiary complex with oxygens of S9947 and ICAGEN-4 and residue Thr480. This binding component is absent in the MSD-D block. As S9947 and ICAGEN-4 show faster block with proceeding channel openings, formation of this tertiary complex may increasingly stabilise binding of S9947 and ICAGEN-4, thereby explaining open channel block kinetics of these compounds.


Assuntos
Canal de Potássio Kv1.5/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Sítios de Ligação , Compostos de Bifenilo/química , Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/farmacologia , Relação Dose-Resposta a Droga , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Cinética , Potássio/farmacologia , Bloqueadores dos Canais de Potássio/química , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia , Fatores de Tempo
8.
J Clin Invest ; 117(5): 1119-27, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17476341

RESUMO

T cell-mediated autoimmune diseases such as multiple sclerosis and rheumatoid arthritis are driven by autoaggressive Th cells. The pathogenicity of such Th cells has, in the past, been considered to be dictated by their cytokine polarization profile. The polarization of such effector T cells relies critically upon the actions of cytokines secreted by APCs. While Th1 polarization has long been associated with the pathogenesis of autoimmune diseases, recent data obtained in gene-targeted mice and the discovery of Th17 cell involvement in autoimmunity conflict with this hypothesis. In light of these recent developments, we discuss in this review the actions of APC-derived cytokines and their emerging roles in T cell polarization in the context of autoimmune inflammatory responses.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Citocinas/fisiologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Animais , Células Apresentadoras de Antígenos/patologia , Citocinas/biossíntese , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Subpopulações de Linfócitos T/classificação
9.
Proc Natl Acad Sci U S A ; 103(49): 18697-702, 2006 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-17121989

RESUMO

The precise mechanisms leading to CNS inflammation and myelin destruction in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) remain the subject of intense debate. In both MS and EAE, autoantibodies (autoAbs) are thought to be involved in tissue destruction through recruiting Fc receptor (FcR)-bearing cells or direct cytotoxic effects through the activation of the complement pathway. Whereas intrathecal immunoglobulin (Ig) production and Ig deposition in inflammatory lesions is a hallmark of MS, mice deficient in B cells and Igs develop severe EAE. Paradoxically, mice of the same genetic background but deficient in FcRgamma are EAE-resistant. We found that the functional expression of FcRgamma on systemic accessory cells, but not CNS-resident cells, appears to be vital for the development of CNS inflammation, independent of antigen-presenting cell function or Ab involvement. On the other hand, we found that the injection of antimyelin oligodendrocyte glycoprotein-Abs drastically worsens disease severity, inflammation, and demyelination. Using FcRgamma(-/-) and C1q(-/-) mice, we could definitively establish that the demyelinating capacity of such autoAb in vivo relies entirely on complement activation and is FcR-independent.


Assuntos
Autoanticorpos/fisiologia , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/fisiologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Receptores de IgG/fisiologia , Animais , Ativação do Complemento/genética , Encefalomielite Autoimune Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de IgG/deficiência , Receptores de IgG/genética
10.
Nat Immunol ; 7(9): 946-53, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16906165

RESUMO

T helper type 1 (T(H)1) lymphocytes are considered to be the main pathogenic cell type responsible for organ-specific autoimmune inflammation. As interleukin 18 (IL-18) is a cofactor with IL-12 in promoting T(H)1 cell development, we examined the function of IL-18 and its receptor, IL-18R, in autoimmune central nervous system inflammation. Similar to IL-12-deficient mice, IL-18-deficient mice were susceptible to experimental autoimmune encephalomyelitis. In contrast, IL-18R alpha-deficient mice were resistant to experimental autoimmune encephalomyelitis, indicating involvement of an IL-18R alpha ligand other than IL-18 with encephalitogenic properties. Moreover, engagement of IL-18R alpha on antigen-presenting cells was required for the generation of pathogenic IL-17-producing T helper cells. Thus, IL-18 and T(H)1 cells are dispensable, whereas IL-18R alpha and IL-17-producing T helper cells are required, for autoimmune central nervous system inflammation.


Assuntos
Encefalomielite Autoimune Experimental/genética , Interleucina-17/metabolismo , Receptores de Interleucina-18/fisiologia , Células Th1/imunologia , Animais , Células Apresentadoras de Antígenos/química , Células Apresentadoras de Antígenos/imunologia , Antígenos/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Interleucina-12/metabolismo , Interleucina-18/genética , Interleucina-18/fisiologia , Interleucina-23/metabolismo , Camundongos , Camundongos Knockout , Mitógenos/imunologia , Receptores de Interleucina-18/análise , Receptores de Interleucina-18/genética
11.
J Clin Invest ; 116(2): 456-64, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16440059

RESUMO

Inflammatory diseases of the CNS, such as MS and its animal model EAE, are characterized by infiltration of activated lymphocytes and phagocytes into the CNS. Within the CNS, activation of resident cells initiates an inflammatory cascade, leading to tissue destruction, demyelination, and neurologic deficit. TLRs recognize microbes and are pivotal mediators of innate immunity. Within the CNS, augmented TLR expression during EAE is observed, even in the absence of any apparent microbial involvement. To determine the functional relevance of this phenomenon during sterile autoimmunity, we studied the role of different TLRs as well as their common signaling adaptor MyD88 in the development of EAE. We found that MyD88 mice were completely EAE resistant. Surprisingly, this protection is partly due to engagement of the CpG receptor TLR9. Restricting the MyD88 or TLR9 mutation to host radio-resistant cells, including the cells within the CNS, revealed that engagement of radio-resistant cells modulated the disease course and histopathological changes. Our data clearly demonstrate that both TLR9 and MyD88 are essential modulators of the autoimmune process during the effector phase of disease and suggest that endogenous "danger signals" modulate the disease pathogenesis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Encefalomielite Autoimune Experimental , Imunidade Inata/fisiologia , Receptor Toll-Like 9/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Transferência Adotiva , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Genótipo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide , Transdução de Sinais/fisiologia , Linfócitos T/imunologia , Linfócitos T/transplante , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Receptor Toll-Like 9/genética , Quimeras de Transplante
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