Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 27
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Cancer Immunol Res ; 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38701369

RESUMO

Glutamine metabolism in tumor microenvironments critically regulates anti-tumor immunity. Using glutamine-antagonist prodrug JHU083, we report potent tumor growth inhibition in urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes (TIMs). We show JHU083-mediated glutamine antagonism in tumor microenvironments induces TNF, pro-inflammatory, and mTORC1 signaling in intratumoral TAM clusters. JHU083-reprogrammed TAMs also exhibit increased tumor cell phagocytosis and diminished pro-angiogenic capacities. In vivo inhibition of TAM glutamine consumption resulted in increased glycolysis, a broken TCA cycle, and purine metabolism disruption. Although the anti-tumor effect of glutamine antagonism on tumor-infiltrating T cells was moderate, JHU083 promoted a stem cell-like phenotype in CD8+ T cells and decreased Treg abundance. Finally, JHU083 caused a ubiquitous shutdown in glutamine utilizing metabolic pathways in tumor cells, leading to reduced HIF-1alpha, c-MYC phosphorylation, and induction of tumor cell apoptosis, all key anti-tumor features.

2.
bioRxiv ; 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-37292712

RESUMO

The loss of E-cadherin (E-cad), an epithelial cell adhesion molecule, has been implicated in the epithelial-mesenchymal transition (EMT), promoting invasion and migration of cancer cells and, consequently, metastasis. However, recent studies have demonstrated that E-cad supports the survival and proliferation of metastatic cancer cells, suggesting that our understanding of E-cad in metastasis is far from comprehensive. Here, we report that E-cad upregulates the de novo serine synthesis pathway (SSP) in breast cancer cells. The SSP provides metabolic precursors for biosynthesis and resistance to oxidative stress, critically beneficial for E-cad-positive breast cancer cells to achieve faster tumor growth and more metastases. Inhibition of PHGDH, a rate-limiting enzyme in the SSP, significantly and specifically hampered the proliferation of E-cad-positive breast cancer cells and rendered them vulnerable to oxidative stress, inhibiting their metastatic potential. Our findings reveal that E-cad adhesion molecule significantly reprograms cellular metabolism, promoting tumor growth and metastasis of breast cancers.

3.
Nat Commun ; 14(1): 7427, 2023 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-37973991

RESUMO

As one of the most successful human pathogens, Mycobacterium tuberculosis (Mtb) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a glutamine metabolism antagonist, JHU083, inhibits Mtb proliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomic analysis of lungs from JHU083-treated Mtb-infected mice reveals citrulline accumulation, suggesting elevated nitric oxide (NO) synthesis, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. JHU083-treated macrophages also produce more NO potentiating their antibacterial activity. When tested in an immunocompromised mouse model of Mtb infection, JHU083 loses its therapeutic efficacy suggesting the drug's host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Camundongos , Humanos , Animais , Glutamina/farmacologia , Tuberculose/microbiologia , Antibacterianos/farmacologia
4.
J Immunol ; 211(12): 1767-1782, 2023 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-37947442

RESUMO

Understanding the mechanisms underlying the acquisition and maintenance of effector function during T cell differentiation is important to unraveling how these processes can be dysregulated in the context of disease and manipulated for therapeutic intervention. In this study, we report the identification of a previously unappreciated regulator of murine T cell differentiation through the evaluation of a previously unreported activity of the kinase inhibitor, BioE-1197. Specifically, we demonstrate that liver kinase B1 (LKB1)-mediated activation of salt-inducible kinases epigenetically regulates cytokine recall potential in effector CD8+ and Th1 cells. Evaluation of this phenotype revealed that salt-inducible kinase-mediated phosphorylation-dependent stabilization of histone deacetylase 7 (HDAC7) occurred during late-stage effector differentiation. HDAC7 stabilization increased nuclear HDAC7 levels, which correlated with total and cytokine loci-specific reductions in the activating transcription mark histone 3 lysine 27 acetylation (H3K27Ac). Accordingly, HDAC7 stabilization diminished transcriptional induction of cytokine genes upon restimulation. Inhibition of this pathway during differentiation produced effector T cells epigenetically poised for enhanced cytokine recall. This work identifies a previously unrecognized target for enhancing effector T cell functionality.


Assuntos
Citocinas , Processamento de Proteína Pós-Traducional , Proteínas Serina-Treonina Quinases , Animais , Camundongos , Diferenciação Celular , Citocinas/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo
5.
bioRxiv ; 2023 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-37693379

RESUMO

Immunotherapy is now an integral aspect of cancer therapy. Strategies employing adoptive cell therapy (ACT) have seen the establishment of chimeric antigen receptor (CAR)-T cells using peripheral blood lymphocytes as well as tumor infiltrating lymphocytes (TILs) with significant clinical results. Despite these successes, the limitations of the current strategies are also emerging and novel approaches are needed. The bone marrow (BM) is an immunological niche that houses T cells with specificity for previously encountered antigens, including tumor-associated antigens from certain solid cancers. This study sought to improve our understanding of tumor-specific BM T cells in the context of solid tumors by comparing them with TILs, and to assess whether there is a rationale for using the BM as a source of T cells for ACT against solid malignancies. Herein, we demonstrate that T cells from the BM appear superior to TILs as a source of cells for cellular therapy. Specifically, they possess a memory-enriched phenotype and exhibit improved effector function, greater persistence within a tumor-bearing host, and the capacity for increased tumor infiltration. Taken together, these data provide a foundation for further exploring the BM as a source of tumor-specific T cells for ACT in solid malignancies.

6.
bioRxiv ; 2023 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-36865287

RESUMO

As one of the most successful human pathogens, Mycobacterium tuberculosis (Mtb) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a novel glutamine metabolism antagonist, JHU083, inhibits Mtb proliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomics analysis of lungs from JHU083-treated Mtb-infected mice revealed reduced glutamine levels, citrulline accumulation suggesting elevated NOS activity, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. When tested in an immunocompromised mouse model of Mtb infection, JHU083 lost its therapeutic efficacy suggesting the drug's host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis.

7.
Sci Adv ; 8(46): eabq5925, 2022 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-36383674

RESUMO

6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8+ T cells. DON showed promising efficacy in clinical trials; however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues. In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression; however, DRP-104 had a markedly improved tolerability profile. DRP-104's effect was CD8+ T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.


Assuntos
Neoplasias , Pró-Fármacos , Humanos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Diazo-Oxo-Norleucina/farmacologia , Diazo-Oxo-Norleucina/uso terapêutico , Glutamina/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Neoplasias/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico
8.
Front Oncol ; 12: 1011191, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36203456

RESUMO

Increased glutamine metabolism is a hallmark of many cancer types. In recent years, our understanding of the distinct and diverse metabolic pathways through which glutamine can be utilized has grown more refined. Additionally, the different metabolic requirements of the diverse array of cell types within the tumor microenvironment complicate the strategy of targeting any particular glutamine pathway as cancer therapy. In this Mini-Review, we discuss recent advances in further clarifying the cellular fate of glutamine through different metabolic pathways. We further discuss potential promising strategies which exploit the different requirements of cells in the tumor microenvironment as it pertains to glutamine metabolism in an attempt to suppress cancer growth and enhance anti-tumor immune responses.

9.
Cancer Res Commun ; 2(7): 639-652, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-36052016

RESUMO

Metabolic features of the tumor microenvironment (TME) antagonize anti-tumor immunity. We hypothesized that T cell infiltrated tumors with a known antigen should exhibit superior clinical outcomes, though some fare worse given unfavorable metabolic features leveraging T cell-infiltrated (Thi), human papillomavirus-related (HPV+) head and neck squamous cell carcinomas (HNSC) to test this hypothesis. Expression of 2,520 metabolic genes were analyzed among Thi HPV+ HNSCs stratified by high-risk molecular subtype. RNAseq data from The Cancer Genome Atlas (TCGA; 10 cancer types), single cell RNAseq data, and an immunotherapy-treated melanoma cohort were used to test the association between metabolic gene expression and clinical outcomes and contribution of tumor versus stromal cells to metabolic gene expression. Polyamine (PA) metabolism genes were overexpressed in high-risk, Thi HPV+ HNSCs. Genes involved in PA biosynthesis and transport were associated with T cell infiltration, recurrent or persistent cancer, overall survival status, primary site, molecular subtype, and MYC genomic alterations. PA biogenesis gene sets were associated with tumor intrinsic features while myeloid cells in HPV+ HNSCs were enriched in PA catabolism, regulatory, transport, putrescine, and spermidine gene set expression. PA gene set expression also correlated with IFNγ or cytotoxic T cell ssGSEA scores across TCGA tumor types. PA transport ssGSEA scores were associated with poor survival whereas putrescine ssGSEA scores portended better survival for several tumor types. Thi melanomas enriched in PA synthesis or combined gene set expression exhibited worse anti-PD-1 responses. These data address hurdles to anti-tumor immunity warranting further investigation of divergent polyamine metabolism in the TME.


Assuntos
Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Humanos , Prognóstico , Infecções por Papillomavirus/genética , Putrescina , Imunoterapia , Microambiente Tumoral/genética
10.
J Immunother Cancer ; 10(2)2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35135866

RESUMO

Increasing evidence supports targeting the adenosine pathway in immuno-oncology with several clinical programs directed at adenosine A2 receptor (A2AR, A2BR), CD73 and CD39 in development. Through a cyclic-AMP-mediated intracellular cascade, adenosine shifts the cytokine and cellular profile of the tumor microenvironment away from cytotoxic T cell inflammation toward one of immune tolerance. A perpetuating cycle of tumor cell proliferation, tissue injury, dysregulated angiogenesis, and hypoxia promote adenosine accumulation via ATP catabolism. Adenosine receptor (eg, A2AR, A2BR) stimulation of both the innate and adaptive cellular precursors lead to immunosuppressive phenotypic differentiation. Preclinical work in various tumor models with adenosine receptor inhibition has demonstrated restoration of immune cell function and tumor regression. Given the broad activity but known limitations of anti-programmed cell death protein (PD1) therapy and other checkpoint inhibitors, ongoing studies have sought to augment the successful outcomes of anti-PD1 therapy with combinatorial approaches, particularly adenosine signaling blockade. Preliminary data have demonstrated an optimal safety profile and enhanced overall response rates in several early phase clinical trials with A2AR and more recently CD73 inhibitors. However, beneficial outcomes for both monotherapy and combinations have been mostly lower than expected based on preclinical studies, indicating a need for more nuanced patient selection or biomarker integration that might predict and optimize patient outcomes. In the context of known immuno-oncology biomarkers such as tumor mutational burden and interferon-associated gene expression, a comparison of adenosine-related gene signatures associated with clinical response indicates an underlying biology related to immunosuppression, angiogenesis, and T cell inflammation. Importantly, though, adenosine associated gene expression may point to a unique intratumoral phenotype independent from IFN-γ related pathways. Here, we discuss the cellular and molecular mechanisms of adenosine-mediated immunosuppression, preclinical investigation of adenosine signaling blockade, recent response data from clinical trials with A2AR, CD73, CD39 and PD1/L1 inhibitors, and ongoing development of predictive gene signatures to enhance combinatorial immune-based therapies.


Assuntos
Adenosina/metabolismo , Imunoterapia/métodos , Neoplasias/imunologia , Humanos
11.
Pharmaceutics ; 14(2)2022 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-35214130

RESUMO

The world raced to develop vaccines to protect against the rapid spread of SARS-CoV-2 infection upon the recognition of COVID-19 as a global pandemic. A broad spectrum of candidates was evaluated, with mRNA-based vaccines emerging as leaders due to how quickly they were available for emergency use while providing a high level of efficacy. As a modular technology, the mRNA-based vaccines benefitted from decades of advancements in both mRNA and delivery technology prior to the current global pandemic. The fundamental lessons of the utility of mRNA as a therapeutic were pioneered by Dr. Katalin Kariko and her colleagues, perhaps most notably in collaboration with Drew Weissman at University of Pennsylvania, and this foundational work paved the way for the development of the first ever mRNA-based therapeutic authorized for human use, COMIRNATY®. In this Special Issue of Pharmaceutics, we will be honoring Dr. Kariko for her great contributions to the mRNA technology to treat diseases with unmet needs. In this review article, we will focus on the delivery platform, the lipid nanoparticle (LNP) carrier, which allowed the potential of mRNA therapeutics to be realized. Similar to the mRNA technology, the development of LNP systems has been ongoing for decades before culminating in the success of the first clinically approved siRNA-LNP product, ONPATTRO®, a treatment for an otherwise fatal genetic disease called transthyretin amyloidosis. Lessons learned from the siRNA-LNP experience enabled the translation into the mRNA platform with the eventual authorization and approval of the mRNA-LNP vaccines against COVID-19. This marks the beginning of mRNA-LNP as a pharmaceutical option to treat genetic diseases.

12.
Cancer Immunol Res ; 9(3): 255-260, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33648947

RESUMO

The success of immune-checkpoint blockade and chimeric antigen receptor (CAR) T cell therapies has established the remarkable capacity of the immune system to fight cancer. Over the past several years, it has become clear that immune cell responses to cancer are critically dependent upon metabolic programs that are specific to both immune cell type and function. Metabolic features of cancer cells and the tumor microenvironment impose constraints on immune cell metabolism that can favor immunosuppressive phenotypes and block antitumor responses. Advances in both preclinical and clinical studies have demonstrated that metabolic interventions can dramatically enhance the efficacy of immune-based therapies for cancer. As such, understanding the metabolic requirements of immune cells in the tumor microenvironment, as well as the limitations imposed therein, can have significant benefits for informing both current practice and future research in cancer immunotherapy.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Microambiente Tumoral/efeitos dos fármacos , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada/métodos , Modelos Animais de Doenças , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento , Evasão Tumoral , Microambiente Tumoral/imunologia , Efeito Warburg em Oncologia/efeitos dos fármacos
13.
Nat Rev Cancer ; 20(9): 516-531, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32632251

RESUMO

Through the successes of checkpoint blockade and adoptive cellular therapy, immunotherapy has become an established treatment modality for cancer. Cellular metabolism has emerged as a critical determinant of the viability and function of both cancer cells and immune cells. In order to sustain prodigious anabolic needs, tumours employ a specialized metabolism that differs from untransformed somatic cells. This metabolism leads to a tumour microenvironment that is commonly acidic, hypoxic and/or depleted of critical nutrients required by immune cells. In this context, tumour metabolism itself is a checkpoint that can limit immune-mediated tumour destruction. Because our understanding of immune cell metabolism and cancer metabolism has grown significantly in the past decade, we are on the cusp of being able to unravel the interaction of cancer cell metabolism and immune metabolism in therapeutically meaningful ways. Although there are metabolic processes that are seemingly fundamental to both cancer and responding immune cells, metabolic heterogeneity and plasticity may serve to distinguish the two. As such, understanding the differential metabolic requirements of the diverse cells that comprise an immune response to cancer offers an opportunity to selectively regulate immune cell function. Such a nuanced evaluation of cancer and immune metabolism can uncover metabolic vulnerabilities and therapeutic windows upon which to intervene for enhanced immunotherapy.


Assuntos
Sistema Imunitário/metabolismo , Neoplasias/metabolismo , Animais , Humanos , Sistema Imunitário/imunologia , Imunoterapia , Neoplasias/genética , Neoplasias/imunologia , Microambiente Tumoral
14.
J Clin Invest ; 130(7): 3865-3884, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32324593

RESUMO

Myeloid cells comprise a major component of the tumor microenvironment (TME) that promotes tumor growth and immune evasion. By employing a small-molecule inhibitor of glutamine metabolism, not only were we able to inhibit tumor growth, but we markedly inhibited the generation and recruitment of myeloid-derived suppressor cells (MDSCs). Targeting tumor glutamine metabolism led to a decrease in CSF3 and hence recruitment of MDSCs as well as immunogenic cell death, leading to an increase in inflammatory tumor-associated macrophages (TAMs). Alternatively, inhibiting glutamine metabolism of the MDSCs themselves led to activation-induced cell death and conversion of MDSCs to inflammatory macrophages. Surprisingly, blocking glutamine metabolism also inhibited IDO expression of both the tumor and myeloid-derived cells, leading to a marked decrease in kynurenine levels. This in turn inhibited the development of metastasis and further enhanced antitumor immunity. Indeed, targeting glutamine metabolism rendered checkpoint blockade-resistant tumors susceptible to immunotherapy. Overall, our studies define an intimate interplay between the unique metabolism of tumors and the metabolism of suppressive immune cells.


Assuntos
Imunidade Celular , Macrófagos/imunologia , Células Supressoras Mieloides/imunologia , Neoplasias Experimentais/imunologia , Microambiente Tumoral/imunologia , Animais , Feminino , Glutamina/imunologia , Imunoterapia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células Supressoras Mieloides/patologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia
15.
Science ; 366(6468): 1013-1021, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31699883

RESUMO

The metabolic characteristics of tumors present considerable hurdles to immune cell function and cancer immunotherapy. Using a glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment of tumors. We demonstrate that glutamine blockade in tumor-bearing mice suppresses oxidative and glycolytic metabolism of cancer cells, leading to decreased hypoxia, acidosis, and nutrient depletion. By contrast, effector T cells responded to glutamine antagonism by markedly up-regulating oxidative metabolism and adopting a long-lived, highly activated phenotype. These divergent changes in cellular metabolism and programming form the basis for potent antitumor responses. Glutamine antagonism therefore exposes a previously undefined difference in metabolic plasticity between cancer cells and effector T cells that can be exploited as a "metabolic checkpoint" for tumor immunotherapy.


Assuntos
Compostos Azo/farmacologia , Caproatos/farmacologia , Glutamina/metabolismo , Imunoterapia Adotiva , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/terapia , Evasão Tumoral , Animais , Linfócitos T CD8-Positivos/imunologia , Ciclo do Ácido Cítrico/efeitos dos fármacos , Metabolismo Energético , Feminino , Glucose/metabolismo , Glutamina/antagonistas & inibidores , Memória Imunológica , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Microambiente Tumoral
16.
J Clin Invest ; 129(11): 4708-4723, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31393856

RESUMO

Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1MUT xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1MUT cancers.


Assuntos
Reprogramação Celular , Mutação , Proteínas de Neoplasias/metabolismo , Neoplasias , Fosfoproteínas , Proteoma/metabolismo , Fatores de Processamento de RNA , Serina , Transcriptoma , Animais , Linhagem Celular Tumoral , Metabolismo Energético/genética , Glicina , Humanos , Camundongos , Proteínas de Neoplasias/genética , Neoplasias/dietoterapia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Fosfoglicerato Desidrogenase/genética , Fosfoglicerato Desidrogenase/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteoma/genética , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Nat Rev Drug Discov ; 18(9): 669-688, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31363227

RESUMO

Metabolic programming is emerging as a critical mechanism to alter immune cell activation, differentiation and function. Targeting metabolism does not completely suppress or activate the immune system but selectively regulates immune responses. The different metabolic requirements of the diverse cells that constitute an immune response provide a unique opportunity to separate effector functions from regulatory functions. Likewise, cells can be metabolically reprogrammed to promote either their short-term effector functions or long-term memory capacity. Studies in the growing field of immunometabolism support a paradigm of 'cellular selectivity based on demand', in which generic inhibitors of ubiquitous metabolic processes selectively affect cells with the greatest metabolic demand and have few effects on other cells of the body. Targeting metabolism, rather than particular cell types or cytokines, in metabolically demanding processes such as autoimmunity, graft rejection, cancer and uncontrolled inflammation could lead to successful strategies in controlling the pathogenesis of these complex disorders.


Assuntos
Autoimunidade/imunologia , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/metabolismo , Imunomodulação/efeitos dos fármacos , Metabolismo/efeitos dos fármacos , Neoplasias/imunologia , Neoplasias/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Modelos Biológicos
18.
Cancer Immunol Immunother ; 67(8): 1271-1284, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29923026

RESUMO

Adenosine signaling via the A2a receptor (A2aR) is emerging as an important checkpoint of immune responses. The presence of adenosine in the inflammatory milieu or generated by the CD39/CD73 axis on tissues or T regulatory cells serves to regulate immune responses. By nature of the specialized metabolism of cancer cells, adenosine levels are increased in the tumor microenvironment and contribute to tumor immune evasion. To this end, small molecule inhibitors of the A2aR are being pursued clinically to enhance immunotherapy. Herein, we demonstrate the ability of the novel A2aR antagonist, CPI-444, to dramatically enhance immunologic responses in models of checkpoint therapy and ACT in cancer. Furthermore, we demonstrate that A2aR blockade with CPI-444 decreases expression of multiple checkpoint pathways, including PD-1 and LAG-3, on both CD8+ effector T cells (Teff) and FoxP3+ CD4+ regulatory T cells (Tregs). Interestingly, our studies demonstrate that A2aR blockade likely has its most profound effects during Teff cell activation, significantly decreasing PD-1 and LAG-3 expression at the draining lymph nodes of tumor bearing mice. In contrast to previous reports using A2aR knockout models, pharmacologic blockade with CPI-444 did not impede CD8 T cell persistence or memory recall. Overall these findings not only redefine our understanding of the mechanisms by which adenosine inhibits immunity but also have important implications for the design of novel immunotherapy regimens.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Neoplasias do Colo/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Melanoma Experimental/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor A2A de Adenosina/química , Receptores de Antígenos de Linfócitos T/metabolismo , Animais , Antígenos CD/química , Antígenos CD/metabolismo , Linfócitos T CD8-Positivos/imunologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Imunoterapia , Linfócitos do Interstício Tumoral , Masculino , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T Reguladores/imunologia , Células Tumorais Cultivadas , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína do Gene 3 de Ativação de Linfócitos
19.
J Immunother Cancer ; 6(1): 57, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29914571

RESUMO

Immune checkpoint antagonists (CTLA-4 and PD-1/PD-L1) and CAR T-cell therapies generate unparalleled durable responses in several cancers and have firmly established immunotherapy as a new pillar of cancer therapy. To extend the impact of immunotherapy to more patients and a broader range of cancers, targeting additional mechanisms of tumor immune evasion will be critical. Adenosine signaling has emerged as a key metabolic pathway that regulates tumor immunity. Adenosine is an immunosuppressive metabolite produced at high levels within the tumor microenvironment. Hypoxia, high cell turnover, and expression of CD39 and CD73 are important factors in adenosine production. Adenosine signaling through the A2a receptor expressed on immune cells potently dampens immune responses in inflamed tissues. In this article, we will describe the role of adenosine signaling in regulating tumor immunity, highlighting potential therapeutic targets in the pathway. We will also review preclinical data for each target and provide an update of current clinical activity within the field. Together, current data suggest that rational combination immunotherapy strategies that incorporate inhibitors of the hypoxia-CD39-CD73-A2aR pathway have great promise for further improving clinical outcomes in cancer patients.


Assuntos
Adenosina/metabolismo , Biomarcadores Tumorais , Neoplasias/imunologia , Neoplasias/metabolismo , Transdução de Sinais , Animais , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Imunomodulação/efeitos dos fármacos , Imunoterapia , Neoplasias/diagnóstico , Neoplasias/terapia , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Evasão Tumoral
20.
Comput Struct Biotechnol J ; 13: 265-72, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25941561

RESUMO

The last several years have witnessed exciting progress in the development of immunotherapy for the treatment of cancer. This has been due in great part to the development of so-called checkpoint blockade. That is, antibodies that block inhibitory receptors such as CTLA-4 and PD-1 and thus unleash antigen-specific immune responses against tumors. It is clear that tumors evade the immune response by usurping pathways that play a role in negatively regulating normal immune responses. In this regard, adenosine in the immune microenvironment leading to the activation of the A2a receptor has been shown to represent one such negative feedback loop. Indeed, the tumor microenvironment has relatively high concentrations of adenosine. To this end, blocking A2a receptor activation has the potential to markedly enhance anti-tumor immunity in mouse models. This review will present data demonstrating the ability of A2a receptor blockade to enhance tumor vaccines, checkpoint blockade and adoptive T cell therapy. Also, as several recent studies have demonstrated that under certain conditions A2a receptor blockade can enhance tumor progression, we will also explore the complexities of adenosine signaling in the immune response. Despite important nuances to the A2a receptor pathway that require further elucidation, studies to date strongly support the development of A2a receptor antagonists (some of which have already been tested in phase III clinical trials for Parkinson Disease) as novel modalities in the immunotherapy armamentarium.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...