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1.
Artigo em Inglês | MEDLINE | ID: mdl-33749106

RESUMO

BACKGROUND: The activating Natural killer group 2 member D (NKG2D) receptor is typically expressed on NK cells, CD8 T lymphocytes, γδ T cells and small subsets of CD4 T lymphocytes. During the course of an extensive flow cytometry phenotyping of immune cells in the peripheral blood of patients with glioblastoma multiforme (GBM) we noticed an unexpected expression of NKG2D receptor on granulocytes using the phycoerythrin (PE)-conjugated clone 149810 antibody. METHODS: Peripheral blood samples from 35 patients with GBM and 22 age-matched healthy control (HC) donors were analyzed using flow cytometry, imaging cytometry and real-time quantitative reverse transcription PCR to validate the observed expression of NKG2D receptor on myeloid cells. RESULTS: Reactivity with PE-149810 was mostly observed on granulocytes from GBM patients on dexamethasone treatment where it correlated with inferior survival rates. Surprisingly, such NKG2D expression on granulocytes was not observed using the allophycocyanin (APC)-conjugate of the same clone 149810 antibody or an indirect staining procedure with unconjugated clone 149810 antibody. Moreover, the PE-conjugate of a different anti-NKG2D clone (1D11) also did not stain granulocytes. Imaging cytometry indicated cell surface and intracellular localization of PE-149810 but not of PE-1D11 in granulocytes. CONCLUSION: Our results uncover an erroneous and false positive reactivity of PE-labeled (but not of APC-labeled or unconjugated) anti-NKG2D antibody 149810 on granulocytes from dexamethasone-treated GBM patients and raise a note of caution for studies of NKG2D expression on non-lymphoid cells.

2.
PLoS Comput Biol ; 17(2): e1008702, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33577569

RESUMO

Intratumour heterogeneity is increasingly recognized as a frequent problem for cancer treatment as it allows for the evolution of resistance against treatment. While cancer genotyping becomes more and more established and allows to determine the genetic heterogeneity, less is known about the phenotypic heterogeneity among cancer cells. We investigate how phenotypic differences can impact the efficiency of therapy options that select on this diversity, compared to therapy options that are independent of the phenotype. We employ the ecological concept of trait distributions and characterize the cancer cell population as a collection of subpopulations that differ in their growth rate. We show in a deterministic model that growth rate-dependent treatment types alter the trait distribution of the cell population, resulting in a delayed relapse compared to a growth rate-independent treatment. Whether the cancer cell population goes extinct or relapse occurs is determined by stochastic dynamics, which we investigate using a stochastic model. Again, we find that relapse is delayed for the growth rate-dependent treatment type, albeit an increased relapse probability, suggesting that slowly growing subpopulations are shielded from extinction. Sequential application of growth rate-dependent and growth rate-independent treatment types can largely increase treatment efficiency and delay relapse. Interestingly, even longer intervals between decisions to change the treatment type may achieve close-to-optimal efficiencies and relapse times. Monitoring patients at regular check-ups may thus provide the temporally resolved guidance to tailor treatments to the changing cancer cell trait distribution and allow clinicians to cope with this dynamic heterogeneity.


Assuntos
Recidiva Local de Neoplasia , Neoplasias/patologia , Algoritmos , Proliferação de Células , Simulação por Computador , Humanos , Imunoterapia , Modelos Genéticos , Modelos Estatísticos , Neoplasias/metabolismo , Fenótipo , Dinâmica Populacional , Processos Estocásticos , Resultado do Tratamento
3.
Expert Rev Hematol ; 13(11): 1211-1233, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33000968

RESUMO

INTRODUCTION: Blinatumomab, first in a class of bispecific T-cell engagers, revolutionized treatment paradigm of B-cell precursor relapsed/refractory or minimal residual disease positive acute lymphoblastic leukemia (ALL) in adults and children, inducing deep remissions in a proportion of patients. However, significant numbers of patients do not respond or eventually relapse. Strategies for improvement of treatment outcomes are required. AREAS COVERED: This review discusses the main structural and functional features of blinatumomab, and its place in the treatment of ALL. Furthermore, prospects to increase the efficacy of blinatumomab are addressed. The developments in the field of bispecific antibodies and their possible implications for treatment of ALL are reviewed. EXPERT OPINION: Better understanding the mechanisms of response and resistance to blinatumomab might help us to identify the group of patients benefiting most from treatment and to spare potentially toxic subsequent treatment strategies. Data emerging from ongoing clinical trials might change the treatment landscape of ALL and beyond. Early use of blinatumomab in frontline protocols with more advantageous treatment sequences and in combination with other targeted therapies might reduce the failure rates. Exponentially increasing number of novel treatment options and their possible combinations might complicate treatment decision-making without data from randomized trials.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Imunoterapia/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/economia , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacocinética , Antígenos CD/análise , Antígenos de Neoplasias/análise , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Ensaios Clínicos como Assunto , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos , Previsões , Humanos , Imunoterapia Adotiva , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prognóstico , Recidiva , Indução de Remissão , Terapia de Salvação , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia
4.
Cell Mol Life Sci ; 77(4): 751-764, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31300870

RESUMO

Dipeptidyl peptidase 4 (DPP4, CD26) is a serine protease detected on several immune cells and on epithelial cells of various organs. Besides the membrane-bound enzyme, a catalytically active soluble form (sCD26/DPP4) is detected in several body fluids. Both variants cleave off dipeptides from the N-termini of various chemokines, neuropeptides, and hormones. CD26/DPP4 plays a fundamental role in the regulation of blood glucose levels by inactivating insulinotropic incretins and CD26/DPP4 inhibitors are thus routinely used in diabetes mellitus type 2 therapy to improve glucose tolerance. Such inhibitors might also prevent the CD26/DPP4-mediated inactivation of the T-cell chemoattractant CXCL10 released by certain tumors and thus improve anti-tumor immunity and immunotherapy. Despite its implication in the regulation of many (patho-)physiological processes and its consideration as a biomarker and therapeutic target, the cellular source of sCD26/DPP4 remains highly debated and mechanisms of its release are so far unknown. In line with recent reports that activated T lymphocytes could be a major source of sCD26/DPP4, we now demonstrate that CD26/DPP4 is stored in secretory granules of several major human cytotoxic lymphocyte populations and co-localizes with effector proteins such as granzymes, perforin, and granulysin. Upon stimulation, vesicular CD26/DPP4 is rapidly translocated to the cell surface in a Ca2+-dependent manner. Importantly, activation-induced degranulation leads to a massive release of proteolytically active sCD26/DPP4. Since activated effector lymphocytes serve as a major source of sCD26/DPP4, these results might explain the observed disease-associated alterations of sCD26/DPP4 serum levels and also indicate a so far unknown role of CD26/DPP4 in lymphocyte-mediated cytotoxicity.


Assuntos
Degranulação Celular , Dipeptidil Peptidase 4/metabolismo , Linfócitos T Citotóxicos/fisiologia , Cálcio/metabolismo , Células Cultivadas , Humanos , Proteólise
5.
Front Immunol ; 10: 569, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30972064

RESUMO

The functional plasticity and anti-tumor potential of human γδ T cells have been widely studied. However, the epigenetic regulation of γδ T-cell/tumor cell interactions has been poorly investigated. In the present study, we show that treatment with the histone deacetylase inhibitor Valproic acid (VPA) significantly enhanced the expression and/or release of the NKG2D ligands MICA, MICB and ULBP-2, but not ULBP-1 in the pancreatic carcinoma cell line Panc89 and the prostate carcinoma cell line PC-3. Under in vitro tumor co-culture conditions, the expression of full length and the truncated form of the NKG2D receptor in γδ T cells was significantly downregulated. Furthermore, using a newly established flow cytometry-based method to analyze histone acetylation (H3K9ac) in γδ T cells, we showed constitutive H3K9aclow and inducible H3K9achigh expression in Vδ2 T cells. The detailed analysis of H3K9aclow Vδ2 T cells revealed a significant reversion of TEMRA to TEM phenotype during in vitro co-culture with pancreatic ductal adenocarcinoma cells. Our study uncovers novel mechanisms of how epigenetic modifiers modulate γδ T-cell differentiation during interaction with tumor cells. This information is important when considering combination therapy of VPA with the γδ T-cell-based immunotherapy for the treatment of certain types of cancer.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Linfócitos Intraepiteliais/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/biossíntese , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Ácido Valproico/farmacologia , Acetilação , Linhagem Celular Tumoral , Proteínas Ligadas por GPI/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Histonas/metabolismo , Humanos , Memória Imunológica/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ativação Linfocitária/imunologia , Masculino , Células PC-3 , Neoplasias Pancreáticas/imunologia , Neoplasias da Próstata/imunologia
6.
Thorac Cardiovasc Surg ; 67(S 04): e11-e18, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31893463

RESUMO

BACKGROUND: Neonates undergoing surgery for complex congenital heart disease are at risk of developmental impairment. Hypoxic-ischemic brain injury might be a contributing factor. We aimed to investigate the perioperative release of the astrocyte cytoskeleton component glial fibrillary acid protein and its relation to cerebral oxygenation. METHODS: Serum glial fibrillary acid protein levels were measured before and 0, 12, 24, and 48 hours after surgery. Reference values were based on preoperative samples; concentrations above the 95th percentile were defined as elevated. Cerebral oxygenation was derived by near-infrared spectroscopy. RESULTS: Thirty-six neonates undergoing 38 surgeries utilizing cardiopulmonary bypass were enrolled (complete data available for 35 procedures). Glial fibrillary acid protein was elevated after 18 surgeries (arterial switch: 7/12; Norwood: 5/15; others: 6/8; p = 0.144). Age at surgery was higher in cases with elevated serum levels (6 [4-7] vs. 4 [2-5] days, p = 0.009) and intraoperative cerebral oxygen saturation was lower (70 ± 10% vs. 77 ± 7%, p = 0.029). In cases with elevated postoperative glial fibrillary acid protein, preoperative cerebral oxygen saturation was lower for neonates undergoing the arterial switch operation (55 ± 9% vs. 64 ± 4%, p = 0.048) and age at surgery was higher for neonates with a Norwood procedure (7 [6-8] vs. 5 [4-6] days, p = 0.028). CONCLUSIONS: Glial fibrillary acid protein was elevated after ∼50% of neonatal cardiac surgeries and was related to cerebral oxygenation and older age at surgery. The potential value as a biomarker for cerebral injury after neonatal cardiac surgery warrants further investigation; in particular, the association with neurodevelopmental outcome needs to be determined.


Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Circulação Cerebrovascular , Proteína Glial Fibrilar Ácida/sangue , Cardiopatias Congênitas/cirurgia , Hipóxia-Isquemia Encefálica/sangue , Hipóxia-Isquemia Encefálica/etiologia , Oxigênio/sangue , Fatores Etários , Biomarcadores/sangue , Ponte Cardiopulmonar/efeitos adversos , Cardiopatias Congênitas/diagnóstico , Humanos , Hipóxia-Isquemia Encefálica/diagnóstico , Hipóxia-Isquemia Encefálica/fisiopatologia , Recém-Nascido , Projetos Piloto , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima
7.
Histochem Cell Biol ; 149(3): 219-233, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29356965

RESUMO

Glioblastoma multiforme (GBM) is a highly malignant brain tumor. Tumor stem cells have a major influence on tumor malignancy, and immunological escape mechanisms, involving the Natural Killer Group 2, member D (NKG2D) receptor-ligand-system, are key elements in tumor immuno-surveillance. We analyzed the expression profile and localization of NKG2D ligands (NKG2DL) and embryonic and neural stem cell markers in solid human GBM and stem-like cells isolated from glioma cell lines by qRT-PCR and immunohistochemistry, including quantitative analysis. We also evaluated the effect of Temozolomide (TMZ), the standard chemotherapeutic agent used in GBM therapy, on NKG2DL expression. NKG2DL-positive cells were mostly found scattered and isolated, were detectable in glial fibrillary acidic protein (GFAP)-positive tumor regions and partly in the penumbra of tumor vessels. NKG2DL were found in a distinct tumor stem-like cell subpopulation and were broadly costained with each other. Quantitative analysis revealed, that dependent on the individual NKG2DL investigated, cell portions costained with different stem cell markers varied between small (Musashi-1) and high (KLf-4) amounts. However, a costaining of NKG2DL with CD3γ, typically found in T cells, was also observable, whereas CD11b as a marker for tumor micoglia cells was only rarely costained with NKG2DL. Stem-like cells derived from the glioma cell lines T98G and U251MG showed a distinct expression pattern of NKG2DL and stem cell markers, which seemed to be balanced in a cell line-specific way. With differentiation, T98G displayed less NKG2DL, whereas in U251MG, only expression of most stem cell markers decreased. In addition, stimulation with TMZ led to a significant upregulation of NKG2DL in stem-like cells of both lines. As stem-like glioma cells tend to show a higher expression of NKG2DL than more differentiated tumor cells and TMZ treatment supports upregulation of NKG2DL, the NKG2D system might play an important role in tumor stem cell survival and in GBM therapy.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioma/metabolismo , Glioma/patologia , Ligantes , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Adulto , Idoso , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Dacarbazina/análogos & derivados , Dacarbazina/química , Dacarbazina/farmacologia , Feminino , Glioma/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Temozolomida , Células Tumorais Cultivadas
8.
Oncoimmunology ; 6(11): e1358839, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29147621

RESUMO

Despite aggressive treatment regimens based on surgery and radiochemotherapy, the prognosis of patients with grade IV glioblastoma multiforme (GBM) remains extremely poor, calling for alternative options such as immunotherapy. Immunological mechanisms including the Natural Killer Group 2 member D (NKG2D) receptor-ligand system play an important role in tumor immune surveillance and targeting the NKG2D system might be beneficial. However, before considering any kind of immunotherapy, a precise characterization of the immune system is important, particularly in GBM patients where conventional therapies with impact on the immune system are frequently co-administered. Here we performed an in-depth immunophenotyping of GBM patients and age-matched healthy controls and analyzed NKG2D ligand expression on primary GBM cells ex vivo. We report that GBM patients have a compromised innate immune system irrespective of steroid (dexamethasone) medication. However, dexamethasone drastically reduced the number of immune cells in the blood of GBM patients. Moreover, higher counts of immune cells influenced by dexamethasone like CD45+ lymphocytes and non-Vδ2 γδ T cells were associated with better overall survival. Higher levels of NKG2D ligands on primary GBM tumor cells were observed in patients who received radiochemotherapy, pointing towards increased immunogenic potential of GBM cells following standard radiochemotherapy. This study sheds light on how steroids and radiochemotherapy affect immune cell parameters of GBM patients, a pre-requisite for the development of new therapeutic strategies targeting the immune system in these patients.

9.
Trends Immunol ; 38(9): 668-678, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28709825

RESUMO

γδ T cells play a role in immune surveillance because they recognize stress-induced surface molecules and metabolic intermediates that are frequently dysregulated in transformed cells. Hence, γδ T cells have attracted much interest as effector cells in cell-based immunotherapy. Recently, however, it has been realized that γδ T cells can also promote tumorigenesis through various mechanisms including regulatory activity and IL-17 production. In this review we outline both the pathways involved in cancer cell recognition and killing by γδ T cells as well as current evidence for their protumorigenic activity in various models. Finally, we discuss strategies to improve the tumor reactivity of γδ T cells and to counteract their protumorigenic activities, which should open improved perspectives for their clinical application.


Assuntos
Imunoterapia/métodos , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/imunologia , Antígeno B7-H1/metabolismo , Carcinogênese , Humanos , Vigilância Imunológica , Imunomodulação , Interleucina-17/metabolismo , Neoplasias/terapia
10.
Oncoimmunology ; 5(4): e1093276, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27141377

RESUMO

The interaction of the MHC class I-related chain molecules A and B (MICA and MICB) and UL-16 binding protein (ULBP) family members expressed on tumor cells with the corresponding NKG2D receptor triggers cytotoxic effector functions in NK cells and γδ T cells. However, as a mechanism of tumor immune escape, NKG2D ligands (NKG2DLs) can be released from the cell surface. In this study, we investigated the NKG2DL system in different human glioblastoma (GBM) cell lines, the most lethal brain tumor in adults. Flow cytometric analysis and ELISA revealed that despite the expression of various NKG2DLs only ULBP2 is released as a soluble protein via the proteolytic activity of "a disintegrin and metalloproteases" (ADAM) 10 and 17. Moreover, we report that temozolomide (TMZ), a chemotherapeutic agent in clinical use for the treatment of GBM, increases the cell surface expression of NKG2DLs and sensitizes GBM cells to γδ T cell-mediated lysis. Both NKG2D and the T-cell receptor (TCR) are involved. The cytotoxic activity of γδ T cells toward GBM cells is strongly enhanced in a TCR-dependent manner by stimulation with pyrophosphate antigens. These data clearly demonstrate the complexity of mechanisms regulating NKG2DL expression in GBM cells and further show that treatment with TMZ can increase the immunogenicity of GBM. Thus, TMZ might enhance the potential of the adoptive transfer of ex vivo expanded γδ T cells for the treatment of malignant glioblastoma.

11.
Exp Eye Res ; 131: 29-41, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25533679

RESUMO

The anti-VEGF antibody bevacizumab is widely used off-label for the treatment of various ocular diseases, most commonly in age-related macular degeneration and diabetic macular edema. Bevacizumab is able to penetrate the retina and is found in the choroid after intravitreal injection in a time dependent manner. It has previously been shown to be taken up by the retinal pigment epithelium (RPE). In this study, we have investigated the intracellular pathway following uptake of bevacizumab in RPE cells, tested both in primary porcine RPE cells and in the human cell line ARPE19. Bevacizumab displays a characteristic, time-dependent pattern of intracellular distribution, as detected by immunofluorescence and pulse chase experiments. In both primary cells and the cell line, intracellular bevacizumab can be found after seven days, as detected by immunofluorescence and Western blotting. Immediately after application, bevacizumab partially colocalizes with Rab5, indicating some uptake in early endosomes. Intracellularly, bevacizumab is detected in the cytoskeletal fraction, aligning with actin filaments, as revealed by subcellular fractioning and immunofluorescence. Bevacizumab seems to travel along actin filaments by myosin7a, as determined by triple staining immunofluorescence. Interestingly, over a period of seven days, bevacizumab seems to accumulate in certain storage areas, as observed by immunofluorescence. Furthermore, results obtained with immunocytochemistry, Western blotting and flow cytometry indicate that bevacizumab may be released from the RPE cells via exosomes. In conclusion, bevacizumab is taken up by and transported in the retinal pigment epithelial cells in a characteristic, time-dependent manner, where it seems to move along actin filaments by myosin7a and seem to be partially released from the cells via exosomes.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Degeneração Macular/tratamento farmacológico , Epitélio Pigmentado da Retina/metabolismo , Inibidores da Angiogênese/farmacocinética , Animais , Bevacizumab , Western Blotting , Células Cultivadas , Modelos Animais de Doenças , Exossomos/metabolismo , Humanos , Imuno-Histoquímica , Líquido Intracelular/metabolismo , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/patologia , Suínos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
12.
Int J Cancer ; 133(7): 1557-66, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23526433

RESUMO

The interaction of the MHC class I-related chain molecules A and B (MICA and MICB) with the corresponding natural killer group 2, member D (NKG2D) receptor triggers cytotoxic effector activity of natural killer cells and certain T-cell subsets and provides a costimulatory signal for cytokine production. Thus, the presence of MICA/B on transformed cells contributes to tumor immunosurveillance. Consequently, the proteolytic cleavage of MICA/B is regarded as an important immune escape mechanism of various cancer cells. To investigate the molecular machinery responsible for the shedding of endogenous MICA/B, we analyzed different human tumor entities including mammary, pancreatic and prostate carcinomas. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) revealed that all tested tumor cells constitutively expressed MICA and MICB on the cell surface and also released NKG2D ligands into the supernatant. We demonstrate that the "a disintegrin and metalloproteases" (ADAMs) 10 and 17 are largely responsible for the generation of soluble MICA/B. Pharmacological inhibition of metalloproteases reduced the level of released MICA/B and increased cell surface expression. Studies using RNA interference not only revealed a prominent role of ADAM10 and ADAM17 in NKG2D ligand shedding but also a tumor cell-specific role of ADAM10 and/or ADAM17 in shedding of MICA or MICB. Moreover, we report that in the prostate carcinoma cell line PC-3, MICA was not shed at all but rather was secreted in exosomes. These data indicate that the release of NKG2D ligands from individual tumor entities is by far more complex than suggested in previously reported MICA/B transfection systems.


Assuntos
Proteínas ADAM/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Proteínas de Membrana/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Neoplasias/imunologia , Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/genética , Proteína ADAM10 , Proteína ADAM17 , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Citocinas/biossíntese , Dipeptídeos/farmacologia , Exossomos , Feminino , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Vigilância Imunológica , Células Matadoras Naturais/imunologia , Masculino , Inibidores de Metaloproteinases de Matriz/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Neoplasias/metabolismo , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Subpopulações de Linfócitos T/imunologia , Tetraspanina 29/metabolismo , Evasão Tumoral/imunologia
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