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1.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805598

RESUMO

Metastasis to the bone is a common feature of many cancers including those of the breast, prostate, lung, thyroid and kidney. Once tumors metastasize to the bone, they are essentially incurable. Bone metastasis is a complex process involving not only intravasation of tumor cells from the primary tumor into circulation, but extravasation from circulation into the bone where they meet an environment that is generally suppressive of their growth. The bone microenvironment can inhibit the growth of disseminated tumor cells (DTC) by inducing dormancy of the DTC directly and later on following formation of a micrometastatic tumour mass by inhibiting metastatic processes including angiogenesis, bone remodeling and immunosuppressive cell functions. In this review we will highlight some of the mechanisms mediating DTC dormancy and the complex relationships which occur between tumor cells and bone resident cells in the bone metastatic microenvironment. These inter-cellular interactions may be important targets to consider for development of novel effective therapies for the prevention or treatment of bone metastases.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/prevenção & controle , Regulação Neoplásica da Expressão Gênica , Neovascularização Patológica/prevenção & controle , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/genética , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/patologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/imunologia , Osso e Ossos/patologia , Comunicação Celular , Citocinas/genética , Citocinas/metabolismo , Humanos , Metástase Linfática , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/imunologia , Osteoblastos/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteoclastos/patologia , Transdução de Sinais , Evasão Tumoral/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fatores de Crescimento do Endotélio Vascular/genética , Fatores de Crescimento do Endotélio Vascular/metabolismo
2.
Cancer Invest ; 39(4): 310-314, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33428503

RESUMO

Diagnosis by biopsy is difficult in the ovary since it is located deep in the abdomen. As a result, ovarian cancer is mostly found insidiously during exploratory laparotomy. Consequently, the early diagnosis of ovarian cancer is often difficult. The likelihood of peritoneal dissemination increases with the progress of ovarian cancer. With further progression, ovarian cancer metastasizes to the momentum, retroperitoneal lymph nodes, large intestine, small intestine, diaphragm, spleen, and other organs. Ovarian cancer has been considered a tumor that has a favorable response to chemotherapy, but more effective treatments are still being explored. Tumors use their own immune escape mechanism to evade host immunity. The immune checkpoint (IC) mechanism, one of the immune escape mechanisms, is established by programmed cell death-1 (PD-1)/PD-ligand-1 (PD-L1) communication. It has been shown that inhibiting PD-1/PD-L1 communication in various malignancies produces antitumor effects. However, the antitumor effect of ICI monotherapy on ovarian cancer is limited in actual clinical practice. In this review, we describe a novel cancer immunotherapeutic agent that targets myeloid-derived suppressor cells (MDSCs).


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Células Supressoras Mieloides/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Evasão Tumoral/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Resultado do Tratamento , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/imunologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
Nat Commun ; 12(1): 440, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33469052

RESUMO

The main challenges for programmed cell death 1(PD-1)/PD-1 ligand (PD-L1) checkpoint blockade lie in a lack of sufficient T cell infiltration, tumor immunosuppressive microenvironment, and the inadequate tumor accumulation and penetration of anti-PD-1/PD-L1 antibody. Resetting tumor-associated macrophages (TAMs) is a promising strategy to enhance T-cell antitumor immunity and ameliorate tumor immunosuppression. Here, mannose-modified macrophage-derived microparticles (Man-MPs) loading metformin (Met@Man-MPs) are developed to efficiently target to M2-like TAMs to repolarize into M1-like phenotype. Met@Man-MPs-reset TAMs remodel the tumor immune microenvironment by increasing the recruitment of CD8+ T cells into tumor tissues and decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and regulatory T cells. More importantly, the collagen-degrading capacity of Man-MPs contributes to the infiltration of CD8+ T cells into tumor interiors and enhances tumor accumulation and penetration of anti-PD-1 antibody. These unique features of Met@Man-MPs contribute to boost anti-PD-1 antibody therapy, improving anticancer efficacy and long-term memory immunity after combination treatment. Our results support Met@Man-MPs as a potential drug to improve tumor resistance to anti-PD-1 therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Micropartículas Derivadas de Células/imunologia , Portadores de Fármacos/farmacologia , Neoplasias/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos , /uso terapêutico , Memória Imunológica , Masculino , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Células RAW 264.7 , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , /imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Phytomedicine ; 80: 153394, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33130472

RESUMO

BACKGROUND: Programmed death-ligand 1 (PD-L1), which can be induced by interferon-gamma (IFN-γ) in the tumor microenvironment, is a critical immune checkpoint in cancer immunotherapy. Natural products which reduce IFN-γ-induced PD-L1 might be exert immunotherapy effect. Licochalcone A (LCA), a natural compound derived from the root of Glycyrrhiza inflata Batalin. (Fabaceae), was found to interfere IFN-γ-induced PD-L1. PURPOSE: The aim of this study is to further clarify the effect and the mechanism of LCA on inhibiting IFN-γ-induced PD-L1 in lung cancer cells. METHODS: The expression levels of PD-L1 were evaluated by flow cytometry, western blot and qRT-PCR. Click-iT protein synthesis assay and luciferase assay were used to identify the effect of LCA on protein synthesis. Jurkat T cell proliferation and apoptosis in the co-culture system were detected by flow cytometry. Flow cytometry was also applied to evaluate reactive oxygen species (ROS) generation. RESULTS: LCA downregulated IFN-γ-induced PD-L1 protein expression and membrane localization in human lung cancer cells, regardless of inhibiting PD-L1 mRNA level or promoting its protein degradation. LCA decreased apoptosis and proliferative inhibition of Jurkat T cells caused by IFN-γ-induced PD-L1-expressing in A549 cells in the co-culture system. Strikingly, LCA was verified as a protein synthesis inhibitor, which reduced both cap-dependent and -independent translation. LCA inhibited PD-L1 translation, likely due to inhibition of 4EBP1 phosphorylation (Ser 65) and activation of PERK-eIF2α pathway. Furthermore, LCA induced ROS generation in a time-dependent manner in lung cancer cells. N-acetyl-L-cysteine (NAC) not only revered ROS generation triggered by LCA but also restored IFN-γ-induced expression of PD-L1. Both the inhibition of 4EBP1 phosphorylation (Ser 65) and activation of PERK-eIF2α axis triggered by LCA was restored by co-treatment with NAC. CONCLUSION: LCA abrogated IFN-γ-induced PD-L1 expression via ROS generation to abolish the protein translation, indicating that LCA has the potential to be applied in cancer immunotherapy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antígeno B7-H1/metabolismo , Chalconas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/efeitos dos fármacos , Antígeno B7-H1/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Interferon gama/metabolismo , Interferon gama/farmacologia , Células Jurkat , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
6.
Nat Commun ; 11(1): 4909, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32999291

RESUMO

Effectively activating macrophages against cancer is promising but challenging. In particular, cancer cells express CD47, a 'don't eat me' signal that interacts with signal regulatory protein alpha (SIRPα) on macrophages to prevent phagocytosis. Also, cancer cells secrete stimulating factors, which polarize tumor-associated macrophages from an antitumor M1 phenotype to a tumorigenic M2 phenotype. Here, we report that hybrid cell membrane nanovesicles (known as hNVs) displaying SIRPα variants with significantly increased affinity to CD47 and containing M2-to-M1 repolarization signals can disable both mechanisms. The hNVs block CD47-SIRPα signaling axis while promoting M2-to-M1 repolarization within tumor microenvironment, significantly preventing both local recurrence and distant metastasis in malignant melanoma models. Furthermore, by loading a stimulator of interferon genes (STING) agonist, hNVs lead to potent tumor inhibition in a poorly immunogenic triple negative breast cancer model. hNVs are safe, stable, drug loadable, and suitable for genetic editing. These properties, combined with the capabilities inherited from source cells, make hNVs an attractive immunotherapy.


Assuntos
Micropartículas Derivadas de Células/imunologia , Imunoterapia/métodos , Macrófagos/imunologia , Melanoma/terapia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias de Mama Triplo Negativas/terapia , Animais , Antígeno CD47/metabolismo , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Melanoma/imunologia , Melanoma/secundário , Proteínas de Membrana/agonistas , Proteínas de Membrana/imunologia , Camundongos , Nanopartículas/administração & dosagem , Recidiva Local de Neoplasia/imunologia , Nucleotídeos Cíclicos/administração & dosagem , Receptores Imunológicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia
7.
Int J Clin Oncol ; 25(10): 1861-1869, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32656742

RESUMO

BACKGROUND: The blockade of cell surface PD-1 ((sur)PD-1) by monoclonal antibodies, represented by nivolumab, provides the strategy to treat advanced malignant melanoma (AMM). The intracellular presence of PD-1 molecules have been reported in some T cell subsets, however, their kinetic association with those expressed on the cell surface, let alone their significance in antitumor immunity has been ill-investigated. METHODS: Intracellular PD-1 expression status in T cell subsets in AMM cases during nivolumab administration was chronologically characterized. The kinetics of PD-1 molecules within AMM-derived T cells was assessed in vitro in conjunction with their functional properties. RESULTS: Increase in (sur)PD-1 and intracellular PD-1 ((int)PD-1+) expression was characteristic for AMM T cells. After short-term culture, virtually (sur)PD-1- nivolumab-treated AMM T cells restore (sur)PD-1 expression, which could not be explained by the detachment of nivolumab from PD-1 epitopes alone. The blockade of trans-Golgi network resulted in the decrease in the extent of (sur)PD-1 recovery, suggesting the translocation of accumulated (int)PD-1 to the cell surface. Antigen-specific PD-1+ T cells significantly increased in (int)PD-1+ cells after treatment. In addition, a surge in (int)PD-1+CD4+ T cells was observed prior to the emergence of skin rash as an immune-related adverse event (irAE). CONCLUSIONS: Accumulated (int)PD-1 in T cells may contribute to enhanced immune evasion in AMM. Evaluation of intracellular PD-1 expression would be useful for better management of nivolumab-treated AMM patients in view of predicting treatment response and the incidence of irAE. Our findings further support the necessity of periodical administration of nivolumab for treating AMM.


Assuntos
Melanoma/imunologia , Nivolumabe/farmacologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/metabolismo , Evasão Tumoral/imunologia , Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Humanos , Imunoterapia/efeitos adversos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Evasão Tumoral/efeitos dos fármacos
8.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188387, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32579889

RESUMO

Late detection, compromised immune system, and chemotherapy resistance underlie the poor patient prognosis for pancreatic ductal adenocarcinoma (PDAC) patients, making it the 3rd leading cause of cancer-related deaths in the United States. Cooperation between the tumor cells and the immune system leads to the immune escape and eventual establishment of the tumor. For more than 20 years, sincere efforts have been made to intercept the tumor-immune crosstalk and identify the probable therapeutic targets for breaking self-tolerance toward tumor antigens. However, the success of these studies depends on detailed examination and understanding of tumor-immune cell interactions, not only in the primary tumor but also at distant systemic niches. Innate and adaptive arms of the immune system sculpt tumor immunogenicity, where they not only aid in providing an amenable environment for their survival but also act as a driver for tumor relapse at primary or distant organ sites. This review article highlights the key events associated with tumor-immune communication and associated immunosuppression at both local and systemic microenvironments in PDAC. Furthermore, we discuss the approaches and benefits of targeting both local and systemic immunosuppression for PDAC patients. The present articles integrate data from clinical and genetic mouse model studies to provide a widespread consensus on the role of local and systemic immunosuppression in undermining the anti-tumor immune responses against PDAC.


Assuntos
Carcinoma Ductal Pancreático/terapia , Imunoterapia/métodos , Neoplasias Pancreáticas/terapia , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Medula Óssea/patologia , Vacinas Anticâncer/administração & dosagem , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Quimioterapia Adjuvante/métodos , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Modelos Animais de Doenças , Intervalo Livre de Doença , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Imunidade Inata/efeitos dos fármacos , Irinotecano/farmacologia , Irinotecano/uso terapêutico , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Excisão de Linfonodo , Linfonodos/imunologia , Linfonodos/patologia , Linfonodos/cirurgia , Camundongos , Camundongos Transgênicos , Terapia Neoadjuvante/métodos , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Pâncreas/imunologia , Pâncreas/patologia , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Baço/imunologia , Baço/patologia , Baço/cirurgia , Esplenectomia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/transplante , Transplante Autólogo/métodos
9.
Cancer Immunol Immunother ; 69(11): 2291-2303, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32504247

RESUMO

Target expression heterogeneity and the presence of an immunosuppressive microenvironment can hamper severely the efficiency of immunotherapeutic approaches. We have analyzed the potential to encounter and overcome such conditions by a combinatory two-target approach involving a bispecific antibody retargeting T cells to tumor cells and tumor-directed antibody-fusion proteins with costimulatory members of the B7 and TNF superfamily. Targeting the tumor-associated antigens EpCAM and EGFR with the bispecific antibody and costimulatory fusion proteins, respectively, we analyzed the impact of target expression and the influence of the immunosuppressive factors IDO, IL-10, TGF-ß, PD-1 and CTLA-4 on the targeting-mediated stimulation of T cells. Here, suboptimal activity of the bispecific antibody at diverse EpCAM expression levels could be effectively enhanced by targeting-mediated costimulation by B7.1, 4-1BBL and OX40L in a broad range of EGFR expression levels. Furthermore, the benefit of combined costimulation by B7.1/4-1BBL and 4-1BBL/OX40L was demonstrated. In addition, the expression of immunosuppressive factors was shown in all co-culture settings, where blocking of prominent factors led to synergistic effects with combined costimulation. Thus, targeting-mediated costimulation showed general promise for a broad application covering diverse target expression levels, with the option for further selective enhancement by the identification and blockade of main immunosuppressive factors of the particular tumor environment.


Assuntos
Anticorpos Biespecíficos/imunologia , Antígenos de Neoplasias/imunologia , Molécula de Adesão da Célula Epitelial/imunologia , Proteínas Recombinantes de Fusão/imunologia , Linfócitos T/imunologia , Anticorpos Biespecíficos/farmacologia , Linhagem Celular Tumoral , Receptores ErbB/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Proteínas Recombinantes de Fusão/farmacologia , Linfócitos T/efeitos dos fármacos , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
10.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188384, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32531324

RESUMO

Cancer regression often fails after systemic immune activation, especially for solid tumors due to their local immunosuppressive microenvironments. Among these, the pancreatic cancer microenvironment is unique and an important reason for resistance to anti-cancer treatments that include immunotherapy. In this review, the three main "BAD" characteristics that create and maintain this immunosuppressive microenvironment are discussed for effector T cells: Barriers to overcome, Attraction problems, and their Disabilities. These inhibit both effector T-cell activation and infiltration, reducing immunotherapy effectiveness. Combination approaches for killing the "BAD" aim to normalize the tumor microenvironment and are recommended to enhance anti-cancer immune-system efficacy in pancreatic cancer.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia Adotiva/métodos , Neoplasias Pancreáticas/terapia , Microambiente Tumoral/efeitos dos fármacos , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Resultado do Tratamento , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
11.
Nature ; 581(7806): 100-105, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32376951

RESUMO

Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy1-3. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found5 despite the frequent downregulation of MHC-I expression6-8. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.


Assuntos
Adenocarcinoma/imunologia , Autofagia/imunologia , Carcinoma Ductal Pancreático/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Neoplasias Pancreáticas/imunologia , Evasão Tumoral/imunologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Apresentação do Antígeno/efeitos dos fármacos , Apresentação do Antígeno/imunologia , Autofagia/efeitos dos fármacos , Autofagia/genética , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Linhagem Celular Tumoral , Cloroquina/farmacologia , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Evasão Tumoral/efeitos dos fármacos
12.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188378, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32413572

RESUMO

CRISPR/Cas-based genetic perturbation screens have emerged as powerful tools for large-scale identification of new targets for cancer immunotherapy. Various strategies of CRISPR screen have been used for immune-oncology (IO) target discovery. The genomic sequences targeted by CRISPR/Cas system range from coding sequences to non-coding RNA/DNA, including miRNAs, LncRNAs, circRNAs, promoters, and enhancers, which may be potential targets for future pharmacological and therapeutic interventions. Rapid progresses have been witnessed in finding novel targets for enhancing tumor antigen presentation, sensitizing of tumor cells to immune-mediated cytotoxicity, and reinvigorating tumor-specific T cells by using CRISPR technologies. In combination with other strategies, the detailed characteristics of the targets for immunotherapy have been obtained by CRISPR screen. In this review, we present an overview of recent progresses in the development of CRISPR-based screens for IO target identification and discuss the challenges and possible solutions in this rapidly growing field.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/genética , Sistemas CRISPR-Cas/genética , Descoberta de Drogas/métodos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/imunologia , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Genômica/métodos , Humanos , Terapia de Alvo Molecular/métodos , Neoplasias/genética , Neoplasias/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/genética
13.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188361, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32234508

RESUMO

Ovarian cancer is the leading cause of gynecological cancer-related mortality globally. The majority of ovarian cancer patients suffer from relapse after standard of care therapies and the clinical benefits from cancer therapies are not satisfactory owing to drug resistance. Certain novel drugs targeting the components of tumor microenvironment (TME) have been approved by US Food and Drug Administration in solid cancers. As such, the passion is rekindled to exploit the role of TME in ovarian cancer progression and metastasis for discovery of novel therapeutics for this deadly disease. In the current review, we revisit the recent mechanistic insights into the contributions of TME to the development, progression, prognosis prediction and therapeutic efficacy of ovarian cancer via modulating cancer hallmarks. We also explored potentially promising predictive and prognostic biomarkers for ovarian cancer patients.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/análise , Neoplasias Ovarianas/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Imunidade Adaptativa/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Progressão da Doença , Aprovação de Drogas , Feminino , Humanos , Imunidade Inata/efeitos dos fármacos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Intervalo Livre de Progressão , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Estados Unidos , United States Food and Drug Administration
14.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188356, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32147542

RESUMO

Tumors are characterized by extracellular matrix (ECM) deposition, remodeling, and cross-linking that drive fibrosis to stiffen the stroma and promote malignancy. The stiffened stroma enhances tumor cell growth, survival and migration and drives a mesenchymal transition. A stiff ECM also induces angiogenesis, hypoxia and compromises anti-tumor immunity. Not surprisingly, tumor aggression and poor patient prognosis correlate with degree of tissue fibrosis and level of stromal stiffness. In this review, we discuss the reciprocal interplay between tumor cells, cancer associated fibroblasts (CAF), immune cells and ECM stiffness in malignant transformation and cancer aggression. We discuss CAF heterogeneity and describe its impact on tumor development and aggression focusing on the role of CAFs in engineering the fibrotic tumor stroma and tuning tumor cell tension and modulating the immune response. To illustrate the role of mechanoreciprocity in tumor evolution we summarize data from breast cancer and pancreatic ductal carcinoma (PDAC) studies, and finish by discussing emerging anti-fibrotic strategies aimed at treating cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/patologia , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/imunologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/mortalidade , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/patologia , Ensaios Clínicos como Assunto , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/imunologia , Matriz Extracelular/imunologia , Matriz Extracelular/patologia , Feminino , Fibrose , Humanos , Pâncreas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Prognóstico , Intervalo Livre de Progressão , Resultado do Tratamento , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
15.
Cancer Cell ; 37(3): 324-339.e8, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32183950

RESUMO

Here, we show that tumor ADORA1 deletion suppresses cell growth in human melanoma cell lines in vitro and tumor development in vivo in immune-deficient xenografts. However, this deletion induces the upregulation of PD-L1 levels, which inactivates cocultured T cells in vitro, compromises anti-tumor immunity in vivo, and reduces anti-tumor efficacy in an immune-competent mouse model. Functionally, PD-1 mAb treatment enhances the efficacy of ADORA1-deficient or ADORA1 antagonist-treated melanoma and NSCLC immune-competent mouse models. Mechanistically, we identify ATF3 as the factor transcriptionally upregulating PD-L1 expression. Tumor ATF3 deletion improves the effect of ADORA1 antagonist treatment of melanoma and NSCLC xenografts. We observe higher ADORA1, lower ATF3, and lower PD-L1 expression levels in tumor tissues from nonresponders among PD-1 mAb-treated NSCLC patients.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Antagonistas do Receptor A1 de Adenosina/farmacologia , Antígeno B7-H1/metabolismo , Melanoma/imunologia , Receptor A1 de Adenosina/metabolismo , Evasão Tumoral/efeitos dos fármacos , Antagonistas do Receptor A1 de Adenosina/uso terapêutico , Adulto , Idoso , Animais , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Linhagem Celular Tumoral , Citarabina/metabolismo , Feminino , Humanos , Lomustina/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Masculino , Melanoma/tratamento farmacológico , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mitoxantrona/metabolismo , Prednisona/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Adv Exp Med Biol ; 1248: 651-653, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32185727

RESUMO

The regulation of immune checkpoint is a pivotal mechanism mediating both self-tolerance physiologically and tumor immune evasion pathologically. Along with an increasing number of identified checkpoint ligand-receptor pairs, the complexity of regulation at genetic, epigenetic, transcriptional, translational, and post-translational levels makes it highly challenging to assemble a comprehensive regulatory network. Advanced animal models are required for determining the exact regulatory effects, given the differences in human and mouse immune systems. Our further understanding on checkpoint regulation may energize translational studies aimed to improve cancer immunotherapy, and collaborations between researchers with different expertise would help to tackle existing challenges in this field.


Assuntos
Imunoterapia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Humanos , Camundongos , Neoplasias/genética , Neoplasias/patologia , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/imunologia , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia
17.
Proc Natl Acad Sci U S A ; 117(14): 7961-7970, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32209667

RESUMO

Mixed lineage kinase 3 (MLK3), also known as MAP3K11, was initially identified in a megakaryocytic cell line and is an emerging therapeutic target in cancer, yet its role in immune cells is not known. Here, we report that loss or pharmacological inhibition of MLK3 promotes activation and cytotoxicity of T cells. MLK3 is abundantly expressed in T cells, and its loss alters serum chemokines, cytokines, and CD28 protein expression on T cells and its subsets. MLK3 loss or pharmacological inhibition induces activation of T cells in in vitro, ex vivo, and in vivo conditions, irrespective of T cell activating agents. Conversely, overexpression of MLK3 decreases T cell activation. Mechanistically, loss or inhibition of MLK3 down-regulates expression of a prolyl-isomerase, Ppia, which is directly phosphorylated by MLK3 to increase its isomerase activity. Moreover, MLK3 also phosphorylates nuclear factor of activated T cells 1 (NFATc1) and regulates its nuclear translocation via interaction with Ppia, and this regulates T cell effector function. In an immune-competent mouse model of breast cancer, MLK3 inhibitor increases Granzyme B-positive CD8+ T cells and decreases MLK3 and Ppia gene expression in tumor-infiltrating T cells. Likewise, the MLK3 inhibitor in pan T cells, isolated from breast cancer patients, also increases cytotoxic CD8+ T cells. These results collectively demonstrate that MLK3 plays an important role in T cell biology, and targeting MLK3 could serve as a potential therapeutic intervention via increasing T cell cytotoxicity in cancer.


Assuntos
Neoplasias da Mama/imunologia , Linfócitos do Interstício Tumoral/imunologia , MAP Quinase Quinase Quinases/metabolismo , Neoplasias Mamárias Experimentais/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral/transplante , Ciclofilina A/metabolismo , Feminino , Humanos , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/metabolismo , MAP Quinase Quinase Quinases/antagonistas & inibidores , MAP Quinase Quinase Quinases/genética , Neoplasias Mamárias Experimentais/sangue , Neoplasias Mamárias Experimentais/patologia , Camundongos , Fatores de Transcrição NFATC/metabolismo , Fosforilação/efeitos dos fármacos , Fosforilação/imunologia , Cultura Primária de Células , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/metabolismo , Evasão Tumoral/efeitos dos fármacos
18.
Nat Commun ; 11(1): 790, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034147

RESUMO

APOBEC3B, an anti-viral cytidine deaminase which induces DNA mutations, has been implicated as a mediator of cancer evolution and therapeutic resistance. Mutational plasticity also drives generation of neoepitopes, which prime anti-tumor T cells. Here, we show that overexpression of APOBEC3B in tumors increases resistance to chemotherapy, but simultaneously heightens sensitivity to immune checkpoint blockade in a murine model of melanoma. However, in the vaccine setting, APOBEC3B-mediated mutations reproducibly generate heteroclitic neoepitopes in vaccine cells which activate de novo T cell responses. These cross react against parental, unmodified tumors and lead to a high rate of cures in both subcutaneous and intra-cranial tumor models. Heteroclitic Epitope Activated Therapy (HEAT) dispenses with the need to identify patient specific neoepitopes and tumor reactive T cells ex vivo. Thus, actively driving a high mutational load in tumor cell vaccines increases their immunogenicity to drive anti-tumor therapy in combination with immune checkpoint blockade.


Assuntos
Vacinas Anticâncer/farmacologia , Citidina Desaminase/imunologia , Imunoterapia/métodos , Antígenos de Histocompatibilidade Menor/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , Resistencia a Medicamentos Antineoplásicos , Epitopos/imunologia , Feminino , Humanos , Células Matadoras Naturais/imunologia , Melanoma/imunologia , Melanoma/terapia , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos Endogâmicos C57BL , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , Mutação , Evasão Tumoral/efeitos dos fármacos
20.
Int Immunopharmacol ; 80: 106247, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32007710

RESUMO

Recently, immunotherapy has evolved into a true treatment modality with the approval of PD-1 and PD-L1 inhibitors as the standard care for first-line treatment in patients with non-small cell lung cancer (NSCLC). Until now, for patients with advanced NSCLC, treatment of targeting immune checkpoints reveals a promising survival benefit, and some patients even get long term survive, which creates a paradigm shift in NSCLC treatment. However, many issues or problems are also appearing in clinical practice, such as the lower overall efficacy rate (20-40%), treatment modes, populations choice of immunotherapy, drug resistance, and safety, etc. Thus, in this review, we will mainly summarize and discuss the recent development and confusion of PD-1/PD-L1 inhibitors for advanced NSCLC patients based on current clinical studies.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia/tendências , Neoplasias Pulmonares/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimiorradioterapia/métodos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Mutação , Estadiamento de Neoplasias , Seleção de Pacientes , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
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