RESUMO
Pulmonary arterial hypertension (PAH) is a complex disorder characterized by vascular remodeling and a consequent increase in pulmonary vascular resistance. The histologic hallmarks of PAH include plexiform and neointimal lesions of the pulmonary arterioles, which are composed of dysregulated, apoptosis-resistant endothelial cells and myofibroblasts. Platelet-derived growth factor receptors (PDGFR) α and ß, colony stimulating factor 1 receptor (CSF1R), and mast/stem cell growth factor receptor kit (c-KIT) are closely related kinases that have been implicated in PAH progression. In addition, emerging data indicate significant crosstalk between PDGF signaling and the bone morphogenetic protein receptor type 2 (BMPR2)/transforming growth factor ß (TGFß) receptor axis. This review will discuss the importance of the PDGFR-CSF1R-c-KIT signaling network in PAH pathogenesis, present evidence that the inhibition of all three nodes in this kinase network is a potential therapeutic approach for PAH, and highlight the therapeutic potential of seralutinib, currently in development for PAH, which targets these pathways.
Assuntos
Hipertensão Arterial Pulmonar , Humanos , Células Endoteliais , Hipertensão Pulmonar Primária Familiar , Inibidores de Proteínas Quinases , Receptores Proteína Tirosina Quinases , Proteínas Proto-Oncogênicas c-kitRESUMO
Chronic activation of inflammatory pathways and suppressed interferon are hallmarks of immunosuppressive tumors. Previous studies have shown that CD11b integrin agonists could enhance anti-tumor immunity through myeloid reprograming, but the underlying mechanisms remain unclear. Herein we find that CD11b agonists alter tumor-associated macrophage (TAM) phenotypes by repressing NF-κB signaling and activating interferon gene expression simultaneously. Repression of NF-κB signaling involves degradation of p65 protein and is context independent. In contrast, CD11b agonism induces STING/STAT1 pathway-mediated interferon gene expression through FAK-mediated mitochondrial dysfunction, with the magnitude of induction dependent on the tumor microenvironment and amplified by cytotoxic therapies. Using tissues from phase I clinical studies, we demonstrate that GB1275 treatment activates STING and STAT1 signaling in TAMs in human tumors. These findings suggest potential mechanism-based therapeutic strategies for CD11b agonists and identify patient populations more likely to benefit.
Assuntos
Antígeno CD11b , Neoplasias , Humanos , Antígeno CD11b/agonistas , Imunoterapia , Interferons , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/imunologia , NF-kappa B/metabolismo , Transdução de Sinais , Macrófagos Associados a Tumor/imunologiaRESUMO
Retinoic acid receptor-related orphan receptor γ (RORc, RORγ, or NR1F3) is the nuclear receptor master transcription factor that drives the function and development of IL-17-producing T helper cells (Th17), cytotoxic T cells (Tc17), and subsets of innate lymphoid cells. Activation of RORγ+ T cells in the tumor microenvironment is hypothesized to render immune infiltrates more effective at countering tumor growth. To test this hypothesis, a family of benzoxazines was optimized to provide LYC-55716 (37c), a potent, selective, and orally bioavailable small-molecule RORγ agonist. LYC-55716 decreases tumor growth and enhances survival in preclinical tumor models and was nominated as a clinical development candidate for evaluation in patients with solid tumors.
Assuntos
Antineoplásicos/uso terapêutico , Benzoxazinas/uso terapêutico , Neoplasias/tratamento farmacológico , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Propionatos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Benzoxazinas/síntese química , Benzoxazinas/farmacocinética , Feminino , Macaca fascicularis , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Propionatos/síntese química , Propionatos/farmacocinética , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Activation of RORγ with synthetic small-molecule agonists has been shown to enhance type 17 effector (CD4+ Th17 and CD8+ Tc17 cells) cell functions and decrease immunosuppressive mechanisms, leading to improved antitumor efficacy in adoptive cell transfer and syngeneic murine tumor models. However, whether Tc17 cells possess intrinsic cytotoxicity and the mechanism they use to lyse target cells is controversial. We report here that Tc17 cells were lytic effectors dependent on perforin and granzyme A. In contrast to Tc1 cells, Tc17 cells resisted activation-induced cell death and maintained granzyme A levels, which conferred the ability to lyse target cells in serial encounters. Thus, although the acute lytic capacity of Tc17 cells could be inferior to Tc1 cells, comparable lysis was achieved over time. In addition to direct lytic activity, Tc17 cells infiltrated early into the tumor mass, recruited other CD8+ T cells to the tumor, and enhanced the survival and lytic capability of these cells during repeated target encounters. Synthetic RORγ agonists further augmented Tc17 survival and lytic activity in vitro and in vivo, controlling tumor growth not only through direct cytotoxicity, but also through recruitment and improved function of other effector cells in the tumor microenvironment, which suggests complementary and cooperate activities for effective immunotherapy.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Citotoxicidade Imunológica/imunologia , Imunoterapia Adotiva/métodos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Subpopulações de Linfócitos T/imunologia , Timoma/terapia , Neoplasias do Timo/terapia , Animais , Granzimas/metabolismo , Interleucina-17/imunologia , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Timoma/imunologia , Timoma/patologia , Neoplasias do Timo/imunologia , Neoplasias do Timo/patologiaRESUMO
Adoptive T-cell transfer therapy is an FDA- approved treatment for leukemia that relies on the ex vivo expansion and reinfusion of a patient's immune cells, which can be engineered with a chimeric antigen receptor (CAR) for more efficient tumor recognition. Type 17 T cells, controlled transcriptionally by RORγ, have been reported to mediate potent antitumor effects superior to those observed with conventionally expanded T cells. Here, we demonstrate that addition of a synthetic, small-molecule RORγ agonist during ex vivo expansion potentiates the antitumor activity of human Th17 and Tc17 cells redirected with a CAR. Likewise, ex vivo use of this agonist bolstered the antitumor properties of murine tumor-specific CD4+ and CD8+ T cells. Expansion in the presence of the RORγ agonist enhanced IL17A production without compromising IFNγ secretion in vitroIn vivo, cytokine neutralization studies revealed that IFNγ and IL17A were required to regress murine melanoma tumors. The enhanced antitumor effect of RORγ agonist treatment was associated with recovery of more donor T cells in the tumor and spleen; these cells produced elevated levels of cytokines months after infusion and expressed markers of long-lived stem and central memory cells such as Tcf7 and CD62L. Conversely, untreated cells mainly exhibited effector phenotypes in the tumor. Cured mice previously treated with agonist-primed T cells were protected from tumor rechallenge. Collectively, our work reveals that in vitro treatment with a RORγ agonist generates potent antitumor Type 17 effector cells that persist as long-lived memory cells in vivoSignificance: RORγ agonists can be used in vitro during T-cell expansion to enhance the efficacy of adoptive cell therapy (e.g., CAR-T) and to provide long-term protection against tumors.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/14/3888/F1.large.jpg Cancer Res; 78(14); 3888-98. ©2018 AACR.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Células Th17/imunologia , Transferência Adotiva/métodos , Animais , Linhagem Celular Tumoral , Citocinas/imunologia , Humanos , Imunoterapia Adotiva/métodos , Interferon gama/imunologia , Interleucina-17 , Ativação Linfocitária/imunologia , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCIDRESUMO
RORγt is the key transcription factor controlling the development and function of CD4+ Th17 and CD8+ Tc17 cells. Across a range of human tumors, about 15% of the CD4+ T cell fraction in tumor-infiltrating lymphocytes are RORγ+ cells. To evaluate the role of RORγ in antitumor immunity, we have identified synthetic, small molecule agonists that selectively activate RORγ to a greater extent than the endogenous agonist desmosterol. These RORγ agonists enhance effector function of Type 17 cells by increasing the production of cytokines/chemokines such as IL-17A and GM-CSF, augmenting expression of co-stimulatory receptors like CD137, CD226, and improving survival and cytotoxic activity. RORγ agonists also attenuate immunosuppressive mechanisms by curtailing Treg formation, diminishing CD39 and CD73 expression, and decreasing levels of co-inhibitory receptors including PD-1 and TIGIT on tumor-reactive lymphocytes. The effects of RORγ agonists were not observed in RORγ-/- T cells, underscoring the selective on-target activity of the compounds. In vitro treatment of tumor-specific T cells with RORγ agonists, followed by adoptive transfer to tumor-bearing mice is highly effective at controlling tumor growth while improving T cell survival and maintaining enhanced IL-17A and reduced PD-1 in vivo. The in vitro effects of RORγ agonists translate into single agent, immune system-dependent, antitumor efficacy when compounds are administered orally in syngeneic tumor models. RORγ agonists integrate multiple antitumor mechanisms into a single therapeutic that both increases immune activation and decreases immune suppression resulting in robust inhibition of tumor growth. Thus, RORγ agonists represent a novel immunotherapy approach for cancer.
RESUMO
PIM kinases are a family of three serine/threonine kinases expressed following T cell activation. Using potent selective small molecule antagonists of PIM-1/3 kinases, we demonstrate a potential role for these enzymes in naïve and effector CD4+ T cell activation. PIM-1/3 inhibition prevented CD4+ T cell proliferation by inducing a G0/G1 cell cycle arrest without affecting cellular survival. In the absence of PIM-1/3 kinase activity, naïve CD4+ T cells failed to fully differentiate into effector cells both in vitro and in vivo. Therapeutic dosing of a PIM-1/3 inhibitor was efficacious in a CD4+ T cell-mediated model of inflammatory bowel disease suggesting that PIM-1 and PIM-3 kinase activity contributes to sustained disease severity. These results demonstrate that PIM-1/3 kinases have an important role in CD4+ T cell responses and inhibition of this activity may provide a therapeutic benefit in T cell-mediated diseases.
Assuntos
Linfócitos T CD4-Positivos/enzimologia , Doenças Inflamatórias Intestinais/enzimologia , Proteínas Proto-Oncogênicas c-pim-1/imunologia , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/genética , Processos de Crescimento Celular/imunologia , Sobrevivência Celular/efeitos dos fármacos , Citocinas/biossíntese , Fase G1/efeitos dos fármacos , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Janus Quinases/metabolismo , Ativação Linfocitária , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos SCID , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/genética , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Interactions between PD-1 and its two differentially expressed ligands, PD-L1 and PD-L2, attenuate T cell activation and effector function. To determine the role of these molecules in autoimmune disease of the CNS, PD-1-/-, PD-L1-/- and PD-L2-/- mice were generated and immunized to induce experimental autoimmune encephalomyelitis (EAE). PD-1-/- and PD-L1-/- mice developed more severe EAE than wild type and PD-L2-/- mice. Consistent with this, PD-1-/- and PD-L1-/- cells produced elevated levels of the pro-inflammatory cytokines IFN-gamma, TNF, IL-6 and IL-17. These results demonstrate that interactions between PD-1/PD-L1, but not PD-1/PDL-2, are crucial in attenuating T cell responses in EAE.
Assuntos
Antígenos de Diferenciação/metabolismo , Antígeno B7-1/metabolismo , Encefalomielite Autoimune Experimental/fisiopatologia , Glicoproteínas de Membrana/metabolismo , Peptídeos/metabolismo , Animais , Antígeno B7-H1 , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Glicoproteínas/imunologia , Humanos , Interferon gama/biossíntese , Interleucina-17/biossíntese , Interleucina-6/biossíntese , Linfonodos/metabolismo , Linfonodos/patologia , Ativação Linfocitária , Glicoproteínas de Membrana/deficiência , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/imunologia , Peptídeos/deficiência , Proteína 2 Ligante de Morte Celular Programada 1 , Receptor de Morte Celular Programada 1 , Índice de Gravidade de Doença , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/biossínteseRESUMO
The CD28 and B7 protein families are critical regulators of immune responses and, in the past few years, several new family members have been identified. Preclinical studies exploring the role of members of the CD28 and B7 families support the targeting of these pathways for new therapeutic approaches. Indeed, recent Phase I clinical studies using agonists and antagonists of the CD28/CTLA-4/B7 pathway have shown promise in inflammatory diseases and cancer.
Assuntos
Antígeno B7-1/fisiologia , Antígenos CD28/fisiologia , Ligantes , Receptores de Antígenos/fisiologia , Animais , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/fisiopatologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/fisiopatologia , Receptores de Antígenos/agonistas , Receptores de Antígenos/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacosRESUMO
The B7 family of ligands and receptors plays a critical role in the modulation of immune responses. The B7/cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the more recently identified programmed death ligand/programmed death-1 (PD-L/PD-1) ligand/receptor pairs define pathways that function as rheostats of lymphocyte activation. Analysis of receptor and ligand expression patterns, as well as the phenotype of CTLA-4 or PD-1-deficient mice, strongly suggests that these pathways are nonredundant. Current data suggest that the B7/CTLA-4 pathway functions primarily to attenuate, limit, and/or terminate naïve T-cell activation in secondary lymphoid organs. The PD-L/PD-1 pathway, on the other hand, may primarily attenuate, limit, and/or terminate T-, B-, and myeloid cell activation/effector function at sites of inflammation in the periphery.
Assuntos
Antígenos de Diferenciação/metabolismo , Antígenos de Superfície/metabolismo , Ativação Linfocitária , Animais , Antígenos CD , Antígenos de Diferenciação/química , Antígenos de Diferenciação/imunologia , Antígenos de Superfície/química , Antígenos de Superfície/genética , Antígenos de Superfície/imunologia , Proteínas Reguladoras de Apoptose , Antígeno B7-1/imunologia , Antígeno B7-1/metabolismo , Antígeno CTLA-4 , Humanos , Receptor de Morte Celular Programada 1 , Transdução de SinaisRESUMO
IFNalpha/beta, IL-12, and IL-15 regulate NK cell activation and expansion, but signals triggering resolution of the NK response upon induction of adaptive immunity remain to be defined. We now report that IL-21, a product of activated T cells, may serve this function. Mice lacking IL-21R (IL-21R(-/-)) had normal NK cell development but no detectable responses to IL-21. IL-21 enhanced cytotoxic activity and IFNgamma production by activated murine NK cells but did not support their viability, thus limiting their duration of activation. Furthermore, IL-21 blocked IL-15-induced expansion of resting NK cells, thus preventing the initiation of further innate responses. In contrast, IL-21 enhanced the proliferation, IFNgamma production, and cytotoxic function of CD8(+) effector T cells in an allogeneic MLR. These observations suggest that IL-21 promotes the transition between innate and adaptive immunity.