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1.
Urol Clin North Am ; 47(4): 469-474, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008497

RESUMO

Multiple immunologic platforms have provided minimal impact in patients with metastatic castration-resistant prostate cancer, necessitating that novel approaches continue to be developed. Although checkpoint inhibitors have been largely ineffective, there remain small cohorts of patients who have durable responses but lack the conventional indicators for response to this class of drugs, that is, high mutational burden or significant genomic alterations, as seen in other solid tumors. This article presents an update on the evolution of immunotherapeutics that target a more lethal form of prostate cancer and provides the groundwork for future considerations as to how this field should proceed.


Assuntos
Quinases Ciclina-Dependentes/genética , Regulação Neoplásica da Expressão Gênica , Imunoterapia/métodos , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/terapia , Idoso , Produtos Biológicos/uso terapêutico , Vacinas Anticâncer/administração & dosagem , Quinases Ciclina-Dependentes/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Fenótipo , Medicina de Precisão/métodos , Prognóstico , Neoplasias de Próstata Resistentes à Castração/patologia , Análise de Sobrevida , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos
2.
Urol Clin North Am ; 47(4): 475-485, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008498

RESUMO

Cancer is a highly complex and heterogeneous disease and immunotherapy has shown promise as a therapeutic approach. The increased resolution afforded by single-cell analysis offers the hope of finding and characterizing previously underappreciated populations of cells that could prove useful in understanding cancer progression and treatment. Urologic and prostate cancers are inherently heterogeneous diseases, and the potential for single-cell analysis to help understand and develop immunotherapeutic approaches to treat these diseases is very exciting. In this review, we view cancer immunotherapy through a single-cell lens and discuss the state-of-the-art technologies that enable advances in this field.


Assuntos
Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Microambiente Tumoral/efeitos dos fármacos , Feminino , Previsões , Humanos , Masculino , Terapia de Alvo Molecular/tendências , Prognóstico , Neoplasias da Próstata/patologia , Medição de Risco , Análise de Sequência de DNA , Análise de Sequência de RNA , Análise de Célula Única , Resultado do Tratamento , Microambiente Tumoral/genética , Neoplasias Urológicas/genética , Neoplasias Urológicas/patologia , Neoplasias Urológicas/terapia
3.
Urol Clin North Am ; 47(4): 487-510, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008499

RESUMO

The advent of immunotherapy has revolutionized cancer treatment. Prostate cancer has an immunosuppressive microenvironment and a low tumor mutation burden, resulting in low neoantigen expression. The consensus was that immunotherapy would be less effective in prostate cancer. However, recent studies have reported that prostate cancer does have a high number of DNA damage and repair gene defects. Immunotherapies that have been tested in prostate cancer so far have been mainly vaccines and checkpoint inhibitors. A combination of genomically targeted therapies, with approaches to alleviate immune response and thereby make the tumor microenvironment immunologically hot, is promising.


Assuntos
Produtos Biológicos/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Imunoterapia/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Microambiente Tumoral/efeitos dos fármacos , Idoso , Animais , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/imunologia , Previsões , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Invasividade Neoplásica/patologia , Metástase Neoplásica/genética , Metástase Neoplásica/imunologia , Estadiamento de Neoplasias , Neoplasias da Próstata/genética , Resultado do Tratamento , Microambiente Tumoral/genética
4.
Urol Clin North Am ; 47(4): 511-521, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008500

RESUMO

The age of immuno-oncology has ushered in a rush within the biopharmaceutical industry. This intense focus has been characterized as a frenzy or overhyped, but represents a substantial investment in new products that hope to harness the immune system against cancer. Such agents include next-generation checkpoint antagonists, immune costimulatory agonists, and a diverse array of novel mechanisms of action and therapeutic modalities targeting immune cell types and the interplay of the host and tumor at the immune synapse. This article surveys the clinical development and investment activity with Immuno-Oncology, specifically prostate, kidney, and bladder cancers.


Assuntos
Produtos Biológicos/uso terapêutico , Biotecnologia/tendências , Imunoterapia/métodos , Microambiente Tumoral/efeitos dos fármacos , Neoplasias Urogenitais/imunologia , Neoplasias Urogenitais/terapia , Biotecnologia/métodos , Feminino , Previsões , Humanos , Masculino , Resultado do Tratamento , Microambiente Tumoral/imunologia , Neoplasias Urogenitais/mortalidade , Neoplasias Urogenitais/patologia
5.
Nat Commun ; 11(1): 4951, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009382

RESUMO

Immunogenic cell death (ICD) and tumour-infiltrating T lymphocytes are severely weakened by elevated reactive oxygen species (ROS) in the tumour microenvironment. It is therefore of critical importance to modulate the level of extracellular ROS for the reversal of immunosuppressive environment. Here, we present a tumour extracellular matrix (ECM) targeting ROS nanoscavenger masked by pH sensitive covalently crosslinked polyethylene glycol. The nanoscavenger anchors on the ECM to sweep away the ROS from tumour microenvironment to relieve the immunosuppressive ICD elicited by specific chemotherapy and prolong the survival of T cells for personalized cancer immunotherapy. In a breast cancer model, elimination of the ROS in tumour microenvironment elicited antitumour immunity and increased infiltration of T lymphocytes, resulting in highly potent antitumour effect. The study highlights a strategy to enhance the efficacy of cancer immunotherapy by scavenging extracellular ROS using advanced nanomaterials.


Assuntos
Antineoplásicos/farmacologia , Espaço Extracelular/metabolismo , Depuradores de Radicais Livres/metabolismo , Morte Celular Imunogênica , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular Tumoral , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Proteína HMGB1/metabolismo , Morte Celular Imunogênica/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Polietilenoglicóis/química , Microambiente Tumoral/efeitos dos fármacos
6.
Nat Commun ; 11(1): 4840, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973129

RESUMO

Immunotherapies revolutionized cancer treatment by harnessing the immune system to target cancer cells. However, most patients are resistant to immunotherapies and the mechanisms underlying this resistant is still poorly understood. Here, we report that overexpression of BMP7, a member of the TGFB superfamily, represents a mechanism for resistance to anti-PD1 therapy in preclinical models and in patients with disease progression while on immunotherapies. BMP7 secreted by tumor cells acts on macrophages and CD4+ T cells in the tumor microenvironment, inhibiting MAPK14 expression and impairing pro-inflammatory responses. Knockdown of BMP7 or its neutralization via follistatin in combination with anti-PD1 re-sensitizes resistant tumors to immunotherapies. Thus, we identify the BMP7 signaling pathway as a potential immunotherapeutic target in cancer.


Assuntos
Proteína Morfogenética Óssea 7/genética , Proteína Morfogenética Óssea 7/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imunoterapia/métodos , Neoplasias/metabolismo , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Linfócitos T CD4-Positivos , Linhagem Celular Tumoral , Feminino , Folistatina/metabolismo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Proteína Quinase 14 Ativada por Mitógeno/genética , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Células RAW 264.7 , Proteína Smad1/metabolismo , Transcriptoma , Microambiente Tumoral/efeitos dos fármacos
7.
Lancet Oncol ; 21(9): e419-e430, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32888471

RESUMO

Notable advances have been achieved in the treatment of cancer since the advent of immunotherapy, and immune checkpoint inhibitors have shown clinical benefit across a wide variety of tumour types. Nevertheless, most patients still progress on these treatments, highlighting the importance of unravelling the underlying mechanisms of primary resistance to immunotherapy. A well described biomarker of non-responsiveness to immune checkpoint inhibitors is the absence or low presence of lymphocytes in the tumour microenvironment, so-called cold tumours. There are five mechanisms of action that have the potential to turn cold tumours into so-called hot and inflamed tumours, hence increasing the tumour's responsiveness to immunotherapy-increasing local inflammation, neutralising immunosuppression at the tumour site, modifying the tumour vasculature, targeting the tumour cells themselves, or increasing the frequency of tumour-specific T cells. In this Review, we discuss preclinical data that serves as the basis for ongoing immunotherapy clinical trials for the treatment of non-immunoreactive tumours, as well as reviewing clinical and translational data where available. We explain how improving our understanding of the underlying mechanisms of primary resistance to immunotherapy will help elucidate an increasingly granular view of the tumour microenvironment cellular composition, functional status, and cellular localisation, with the goal of further therapy refinement.


Assuntos
Resistencia a Medicamentos Antineoplásicos/imunologia , Imunoterapia/efeitos adversos , Inflamação/terapia , Neoplasias/terapia , Microambiente Tumoral/efeitos dos fármacos , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Quinase 1 do Ponto de Checagem/imunologia , Ensaios Clínicos como Assunto , Humanos , Imunidade Celular/imunologia , Inflamação/imunologia , Inflamação/patologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Microambiente Tumoral/imunologia
8.
Int J Nanomedicine ; 15: 6311-6324, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922003

RESUMO

Background: Hyaluronic acid (HA) is a major component of extracellular matrix (ECM) and its over expression in tumor tissues contributes to the increase of interstitial fluid pressure (IFP) and hinders the penetration of nanoparticles into solid tumors. Materials and Methods: We here reported a tumoral microenvironment responsive multistage drug delivery system (NPs-EPI/HAase) which was formed layer by layer via electrostatic interaction with epirubicin (EPI)-loaded PEG-b-poly(2-(diisopropylamino)ethyl methacrylate)-b-poly(2-guanidinoethylmethacrylate) (mPEG-PDPA-PG, PEDG) micelles (NPs-EPI) and hyaluronidase (HAase). In this paper, we focused on the hyaluronidase-combined nanoparticles (NPs-EPI/HAase) for tumor penetration in tumor spheroid and solid tumor models in vitro and in vivo. Results: Our results showed that NPs-EPI/HAase effectively degrade the HA in ECM and facilitate deep penetration of NPs-EPI into solid tumor. Moreover, NPs-EPI mainly employed clathrin-mediated and macropinocytosis-mediated endocytic pathways for cellular uptake and were subsequently directed to the lysosomes for further drug release triggered by proton sponge effect. Compared with NPs-EPI, the HAase coating group showed an enhanced tumoral drug delivery efficacy and inhibition of tumor growth. Conclusion: Overall, our studies demonstrated that coating nanoparticles with HAase can provide a simple but efficient strategy for nano-drug carriers to enhance solid tumor penetration and chemotherapeutic efficacy.


Assuntos
Antineoplásicos/uso terapêutico , Hialuronoglucosaminidase/metabolismo , Nanopartículas/química , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Endocitose/efeitos dos fármacos , Epirubicina/farmacologia , Epirubicina/uso terapêutico , Humanos , Antígeno Ki-67/metabolismo , Masculino , Camundongos Nus , Nanopartículas/administração & dosagem , Neoplasias/patologia , Polímeros/química , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
9.
Int J Nanomedicine ; 15: 6451-6468, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922011

RESUMO

Background: Non-small cell lung cancer (NSCLC) is one of the most lethal types of cancer with highly infiltrating. Chemotherapy is far from satisfactory, vasculogenic mimicry (VM) and angiogenesis results in invasion, migration and relapse. Purpose: The objective of this study was to construct a novel CPP (mmp) modified vinorelbine and dioscin liposomes by two new functional materials, DSPE-PEG2000-MAL and CPP-PVGLIG-PEG5000, to destroy VM channels, angiogenesis, EMT and inhibit invasion and migration. Methods and Results: The targeting liposomes could be enriched in tumor sites through passive targeting, and the positively charged CPP was exposed and enhanced active targeting via electrostatic adsorption after being hydrolyzed by MMP2 enzymes overexpressed in the tumor microenvironment. We found that CPP (mmp) modified vinorelbine and dioscin liposomes with the ideal physicochemical properties and exhibited enhanced cellular uptake. In vitro and in vivo results showed that CPP (mmp) modified vinorelbine and dioscin liposomes could inhibit migration and invasion of A549 cells, destroy VM channels formation and angiogenesis, and block the EMT process. Pharmacodynamic studies showed that the targeting liposomes had obvious accumulations in tumor sites and magnificent antitumor efficiency. Conclusion: CPP (mmp) modified vinorelbine plus dioscin liposomes could provide a new strategy for NSCLC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Microambiente Tumoral , Células A549 , Animais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Morte Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Galinhas , Endocitose/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Hidrólise , Lipossomos , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Microambiente Tumoral/efeitos dos fármacos , Vinorelbina/farmacologia , Vinorelbina/uso terapêutico
10.
Anticancer Res ; 40(10): 5509-5516, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988874

RESUMO

BACKGROUND/AIM: Extracellular vesicles (EVs) can mediate drug resistance within the tumor microenvironment by delivering bioactive molecules, including proteins. Here, we performed a comparative proteomic analysis of EVs secreted by A549 lung cancer cells and their cisplatin-resistant counterparts in order to identify proteins involved in drug resistance. MATERIALS AND METHODS: Cells were co-cultivated using a transwell system to evaluate EV exchange. EVs were isolated by ultracentrifugation and analyzed using microscopy and nanoparticle tracking. EV proteome was analyzed by mass spectrometry. RESULTS: EV-mediated communication was observed between co-cultured A549 and A549/CDDP cells. EVs isolated from both cells were mainly exosome-like structures. Extracellular matrix components, cell adhesion proteins, complement factors, histones, proteasome subunits and membrane transporters were found enriched in the EVs released by cisplatin-resistant cells. CONCLUSION: Proteins identified in this work may have a relevant role in modulating the chemosensitivity of the recipient cells and could represent useful biomarkers to monitor cisplatin response in lung cancer.


Assuntos
Biomarcadores Tumorais/genética , Cisplatino/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Proteoma/genética , Células A549 , Cisplatino/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Exossomos/efeitos dos fármacos , Exossomos/genética , Vesículas Extracelulares/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Espectrometria de Massas , Proteômica/métodos , Microambiente Tumoral/efeitos dos fármacos
11.
Nat Commun ; 11(1): 3946, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770055

RESUMO

Melanomas can switch to a dedifferentiated cell state upon exposure to cytotoxic T cells. However, it is unclear whether such tumor cells pre-exist in patients and whether they can be resensitized to immunotherapy. Here, we chronically expose (patient-derived) melanoma cell lines to differentiation antigen-specific cytotoxic T cells and observe strong enrichment of a pre-existing NGFRhi population. These fractions are refractory also to T cells recognizing non-differentiation antigens, as well as to BRAF + MEK inhibitors. NGFRhi cells induce the neurotrophic factor BDNF, which contributes to T cell resistance, as does NGFR. In melanoma patients, a tumor-intrinsic NGFR signature predicts anti-PD-1 therapy resistance, and NGFRhi tumor fractions are associated with immune exclusion. Lastly, pharmacologic NGFR inhibition restores tumor sensitivity to T cell attack in vitro and in melanoma xenografts. These findings demonstrate the existence of a stable and pre-existing NGFRhi multitherapy-refractory melanoma subpopulation, which ought to be eliminated to revert intrinsic resistance to immunotherapeutic intervention.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Melanoma/tratamento farmacológico , Proteínas do Tecido Nervoso/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fator de Crescimento Neural/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Linfócitos T Citotóxicos/imunologia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , RNA-Seq , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Linfócitos T Citotóxicos/metabolismo , Evasão Tumoral/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Nat Commun ; 11(1): 4064, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792542

RESUMO

Regulation of the programming of tumour-associated macrophages (TAMs) controls tumour growth and anti-tumour immunity. We examined the role of FGF2 in that regulation. Tumours in mice genetically deficient in low-molecular weight FGF2 (FGF2LMW) regress dependent on T cells. Yet, TAMS not T cells express FGF receptors. Bone marrow derived-macrophages from Fgf2LMW-/- mice co-injected with cancer cells reduce tumour growth and express more inflammatory cytokines. FGF2 is induced in the tumour microenvironment following fractionated radiation in murine tumours consistent with clinical reports. Combination treatment of in vivo tumours with fractionated radiation and a blocking antibody to FGF2 prolongs tumour growth delay, increases long-term survival and leads to a higher iNOS+/CD206+ TAM ratio compared to irradiation alone. These studies show for the first time that FGF2 affects macrophage programming and is a critical regulator of immunity in the tumour microenvironment.


Assuntos
Fator 2 de Crescimento de Fibroblastos/metabolismo , Radioterapia/métodos , Animais , Linhagem Celular Tumoral , Fator 2 de Crescimento de Fibroblastos/genética , Células HT29 , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/efeitos da radiação , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Life Sci ; 258: 118163, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738363

RESUMO

The tumor microenvironment (TME) provides a guarantee for the survival and development of solid tumors. In recent years, treatment strategies for TME have set off a great upsurge in the field of cancer research. Tumor angiogenesis and tumor immune microenvironment are two important research branches of TME, and antiangiogenic therapy and immunotherapy have gradually become one important focus of cancer treatment research. More interestingly, increasing number of studies have indicated that there are complex regulatory interactions between the two treatment strategies, with multiple regulatory mechanisms involved. Based on these findings, clinical studies on the combination of immunotherapy and antiangiogenic therapy have also been carried out gradually. This combination strategy has shown good results in many types of tumors, but it also faces many challenges. The paper analysed the potential mechanism of the immunotherapy and antiangiogenic therapy combination, discussed the latest significant clinical trial progress and the existing challenges and problems, aiming to offer some available insights on the effective clinical application of this combination pattern.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Imunoterapia/métodos , Neoplasias/terapia , Neovascularização Patológica/terapia , Animais , Terapia Combinada , Humanos , Neoplasias/complicações , Neoplasias/imunologia , Neoplasias/patologia , Neovascularização Patológica/complicações , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Microambiente Tumoral/efeitos dos fármacos
14.
Nat Commun ; 11(1): 3704, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709869

RESUMO

FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. However, effective drugs for treating FGF-2+ tumors are unavailable. Here we show that FGF-2 modulates tumor vessels by recruiting NG2+ pricytes onto tumor microvessels through a PDGFRß-dependent mechanism. FGF-2+ tumors are intrinsically resistant to clinically available drugs targeting VEGF and PDGF. Surprisingly, dual targeting the VEGF and PDGF signaling produces a superior antitumor effect in FGF-2+ breast cancer and fibrosarcoma models. Mechanistically, inhibition of PDGFRß ablates FGF-2-recruited perivascular coverage, exposing anti-VEGF agents to inhibit vascular sprouting. These findings show that the off-target FGF-2 is a resistant biomarker for anti-VEGF and anti-PDGF monotherapy, but a highly beneficial marker for combination therapy. Our data shed light on mechanistic interactions between various angiogenic and remodeling factors in tumor neovascularization. Optimization of antiangiogenic drugs with different principles could produce therapeutic benefits for treating their resistant off-target cancers.


Assuntos
Inibidores da Angiogênese/farmacologia , Fator 2 de Crescimento de Fibroblastos/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/metabolismo , Neoplasias/tratamento farmacológico , Fator de Crescimento Derivado de Plaquetas/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Animais , Biomarcadores Tumorais , Pressão Sanguínea , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Permeabilidade Capilar , Proliferação de Células , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Quimioterapia Combinada , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas , Transdução de Sinais/efeitos dos fármacos , Hipóxia Tumoral , Microambiente Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
15.
Cancer Immunol Immunother ; 69(11): 2169-2178, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32648166

RESUMO

T-cell receptor (TCR)- and chimeric antigen receptor (CAR)-based adoptive cell transfer (ACT) has shown promising results in hematological malignancies, but remains immature in solid cancers. The challenges associated with identification of tumor-specific targets, the heterogenic antigen expression, limited T-cell trafficking to tumor sites and the hostile tumor microenvironment (TME), are all factors contributing to the limited efficacy of ACT therapies against solid tumors. Epigenetic priming of tumor cells and the microenvironment may be a way of overcoming these obstacles and improving the clinical efficacy of adoptive T-cell therapies in the future. Here, we review the current literature and suggest combining epigenetic modulators and ACT strategies as a way of augmenting the efficacy of TCR- and CAR-engineered T cells against solid tumors.


Assuntos
Terapia Combinada/métodos , Epigênese Genética , Imunoterapia Adotiva/métodos , Neoplasias , Linfócitos T/transplante , Animais , Antígenos de Neoplasias/imunologia , Metilases de Modificação do DNA/antagonistas & inibidores , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Evasão Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
16.
Nat Genet ; 52(6): 582-593, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32483290

RESUMO

In metastatic cancer, the degree of heterogeneity of the tumor microenvironment (TME) and its molecular underpinnings remain largely unstudied. To characterize the tumor-immune interface at baseline and during neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSOC), we performed immunogenomic analysis of treatment-naive and paired samples from before and after treatment with chemotherapy. In treatment-naive HGSOC, we found that immune-cell-excluded and inflammatory microenvironments coexist within the same individuals and within the same tumor sites, indicating ubiquitous variability in immune cell infiltration. Analysis of TME cell composition, DNA copy number, mutations and gene expression showed that immune cell exclusion was associated with amplification of Myc target genes and increased expression of canonical Wnt signaling in treatment-naive HGSOC. Following NACT, increased natural killer (NK) cell infiltration and oligoclonal expansion of T cells were detected. We demonstrate that the tumor-immune microenvironment of advanced HGSOC is intrinsically heterogeneous and that chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors.


Assuntos
Cistadenocarcinoma Seroso/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas/tratamento farmacológico , Microambiente Tumoral/imunologia , Animais , Cisplatino/imunologia , Cisplatino/farmacologia , Estudos de Coortes , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Variações do Número de Cópias de DNA , Feminino , Perfilação da Expressão Gênica/estatística & dados numéricos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes myc , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Camundongos , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Análise de Componente Principal , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Via de Sinalização Wnt
17.
Mol Cell ; 78(6): 1019-1033, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32559423

RESUMO

The growing field of immune metabolism has revealed promising indications for metabolic targets to modulate anti-cancer immunity. Combination therapies involving metabolic inhibitors with immune checkpoint blockade (ICB), chemotherapy, radiation, and/or diet now offer new approaches for cancer therapy. However, it remains uncertain how to best utilize these strategies in the context of the complex tumor microenvironment (TME). Oncogene-driven changes in tumor cell metabolism can impact the TME to limit immune responses and present barriers to cancer therapy. These changes also reveal opportunities to reshape the TME by targeting metabolic pathways to favor immunity. Here we explore current strategies that shift immune cell metabolism to pro-inflammatory states in the TME and highlight a need to better replicate physiologic conditions to select targets, clarify mechanisms, and optimize metabolic inhibitors. Unifying our understanding of these pathways and interactions within the heterogenous TME will be instrumental to advance this promising field and enhance immunotherapy.


Assuntos
Imunoterapia/tendências , Neoplasias/metabolismo , Microambiente Tumoral/imunologia , Humanos , Fatores Imunológicos/metabolismo , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Microambiente Tumoral/efeitos dos fármacos
18.
Lancet ; 395(10242): 2008-2020, 2020 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-32593337

RESUMO

Pancreatic cancer is a highly fatal disease with a 5-year survival rate of approximately 10% in the USA, and it is becoming an increasingly common cause of cancer mortality. Risk factors for developing pancreatic cancer include family history, obesity, type 2 diabetes, and tobacco use. Patients typically present with advanced disease due to lack of or vague symptoms when the cancer is still localised. High quality computed tomography with intravenous contrast using a dual phase pancreatic protocol is typically the best method to detect a pancreatic tumour and to determine surgical resectability. Endoscopic ultrasound is an increasingly used complementary staging modality which also allows for diagnostic confirmation when combined with fine needle aspiration. Patients with pancreatic cancer are often divided into one of four categories based on extent of disease: resectable, borderline resectable, locally advanced, and metastatic; patient condition is also an important consideration. Surgical resection represents the only chance for cure, and advancements in adjuvant chemotherapy have improved long-term outcomes in these patients. Systemic chemotherapy combinations including FOLFIRINOX (5-fluorouracil, folinic acid [leucovorin], irinotecan, and oxaliplatin) and gemcitabine plus nab-paclitaxel remain the mainstay of treatment for patients with advanced disease. Data on the benefit of PARP inhibition as maintenance therapy in patients with germline BRCA1 or BRACA2 mutations might prove to be a harbinger of advancement in targeted therapy. Additional research efforts are focusing on modulating the pancreatic tumour microenvironment to enhance the efficacy of the immunotherapeutic strategies.


Assuntos
Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/terapia , Administração Intravenosa , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/efeitos dos fármacos , Proteína BRCA1/genética , Proteína BRCA2/efeitos dos fármacos , Proteína BRCA2/genética , Quimioterapia Adjuvante/métodos , Meios de Contraste/administração & dosagem , Dano ao DNA/efeitos dos fármacos , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Humanos , Imunoterapia/métodos , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Fatores de Risco , Taxa de Sobrevida , Tomografia Computadorizada por Raios X/métodos , Microambiente Tumoral/efeitos dos fármacos
19.
Mol Cell ; 78(6): 1002-1018, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32559422

RESUMO

We are witnessing several revolutionary technological advances in cancer. These innovations have not only contributed to a growing understanding of the tumor and its microenvironment but also uncovered an increasing array of new therapeutic targets. For most advanced cancers, therapy resistance limits the benefit of single-agent therapies. Therefore, some 5,000 clinical trials are ongoing globally to probe the clinical benefit of new combination treatments. However, the possibilities to combine individual treatments dramatically outnumber the patients available to enroll in clinical trials. This comes at a potential cost of missed opportunities, clinical failure, avoidable toxicity, insufficient patient accrual, and financial loss. A solution may be to design combination therapies more rationally, which are informed by fundamental biological and mechanistic insight. We will discuss some successes and failures of current treatment combinations, as well as interesting emerging preclinical concepts that warrant clinical exploration.


Assuntos
Quimioterapia Combinada/tendências , Neoplasias/terapia , Drogas Desenhadas/uso terapêutico , Humanos , Neoplasias/metabolismo , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Microambiente Tumoral/efeitos dos fármacos
20.
Cell Prolif ; 53(8): e12865, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32588948

RESUMO

The tumour microenvironment (TME) plays a pivotal role in tumour fate determination. The TME acts together with the genetic material of tumour cells to determine their initiation, metastasis and drug resistance. Stromal cells in the TME promote the growth and metastasis of tumour cells by secreting soluble molecules or exosomes. The abnormal microenvironment reduces immune surveillance and tumour killing. The TME causes low anti-tumour drug penetration and reactivity and high drug resistance. Tumour angiogenesis and microenvironmental hypoxia limit the drug concentration within the TME and enhance the stemness of tumour cells. Therefore, modifying the TME to effectively attack tumour cells could represent a comprehensive and effective anti-tumour strategy. Normal cells, such as stem cells and immune cells, can penetrate and disrupt the abnormal TME. Reconstruction of the TME with healthy cells is an exciting new direction for tumour treatment. We will elaborate on the mechanism of the TME to support tumours and the current cell therapies for targeting tumours and the TME-such as immune cell therapies, haematopoietic stem cell (HSC) transplantation therapies, mesenchymal stem cell (MSC) transfer and embryonic stem cell-based microenvironment therapies-to provide novel ideas for producing breakthroughs in tumour therapy strategies.


Assuntos
Antineoplásicos/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Exossomos/efeitos dos fármacos , Exossomos/patologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia
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