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1.
Cells ; 10(11)2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34831116

RESUMO

The metabolic changes that occur in tumor microenvironment (TME) can influence not only the biological activity of tumor cells, which become more aggressive and auto sustained, but also the immune response against tumor cells, either producing ineffective responses or polarizing the response toward protumor activity. γδ T cells are a subset of T cells characterized by a plasticity that confers them the ability to differentiate towards different cell subsets according to the microenvironment conditions. On this basis, we here review the more recent studies focused on altered tumor metabolism and γδ T cells, considering their already known antitumor role and the possibility of manipulating their effector functions by in vitro and in vivo approaches. γδ T cells, thanks to their unique features, are themselves a valid alternative to overcome the limits associated with the use of conventional T cells, such as major histocompatibility complex (MHC) restriction, costimulatory signal and specific tumor-associated antigen recognition. Lipids, amino acids, hypoxia, prostaglandins and other metabolic changes inside the tumor microenvironment could reduce the efficacy of this important immune population and polarize γδ T cells toward IL17 producing cells that play a pro tumoral role. A deeper knowledge of this phenomenon could be helpful to formulate new immunotherapeutic approaches that target tumor metabolisms.

2.
Vaccines (Basel) ; 9(6)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071430

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection dysregulates the immune system by lymphopenia of B cells, monocytes, eosinophils, basophils, and cytotoxic cells such as CD8, γδ T cells, and natural killer (NK) cells. Despite many studies being conducted to better understand the effects of SARS-CoV-2 on the immune system, many mechanisms still remain unclear, hindering the development of novel therapeutic approaches and strategies to improve the host's immune defense. This mini-review summarizes the findings on the role of γδ T cells in coronavirus disease 2019 (COVID-19), providing an overview of the excellent anti-viral therapeutic potential of γδ T cells, that had not yet been exploited in depth.

3.
Gene ; 768: 145269, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33148459

RESUMO

Adipose stem cells (ASCs) represent a reliable source of stem cells with a widely demonstrated potential in regenerative medicine and tissue engineering applications. New recent insights suggest that three-dimensional (3D) models may closely mimic the native tissue properties; spheroids from adipose derived stem cells (SASCs) exhibit enhanced regenerative abilities compared with those of 2D models. Stem cell therapy success is determined by "cell-quality"; for this reason, the involvement of stress signals and cellular aging need to be further investigated. Here, we performed a comparative analysis of genes connected with stemness, aging, telomeric length and oxidative stress, in 3D and 2D primary cultures. The expression levels of stemness-related markers and anti-aging Sirtuin1 were significantly up-regulated (P < 0.001) in SASCs-3D while gene expression of aging-related p16INK4a was increased in ASCs-2D (P < 0.001). The 3D and 2D cultures also had a different gene expression profile for genes related to telomere maintenance (Shelterin complex, RNA Binding proteins and DNA repair genes) (P < 0.01 and P < 0.001) and oxidative stress (aldehyde dehydrogenase class1 and 3) (P < 0.05, P < 0.01 and P < 0.001) and presented a striking large variation in their cellular redox state. Based on our findings, we propose a "cell quality" model of SASCs, highlighting a precise molecular expression of several genes involved with stemness (SOX2, POU5F1 and NANOG), anti-aging (SIRT1), oxidative stress (ALDH3) and telomeres maintenance.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/citologia , Técnicas de Cultura de Células , Transplante de Células-Tronco , Células-Tronco/citologia , Adipócitos/citologia , Adolescente , Adulto , Idoso , Envelhecimento/genética , Adesão Celular/genética , Sobrevivência Celular/genética , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Reparo do DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/genética , Proteínas de Ligação a RNA/metabolismo , Sirtuínas/metabolismo , Esferoides Celulares/citologia , Homeostase do Telômero/genética , Engenharia Tecidual/métodos , Adulto Jovem
6.
Immunol Rev ; 298(1): 153-164, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32691450

RESUMO

The finding that γδ T cells are present among tumor-infiltrating lymphocytes in humans suggests they participate in tumor immune surveillance, but their relevance is unclear because the relative abundance of tumor-infiltrating γδ T cells correlates with positive or negative, or even do not correlate with prognosis. This likely depends on the fact that tumor-infiltrating γδ T cells may play substantially different effector or regulatory functions, and correlation with patient's prognosis relies on distinct γδ T cell subsets in the context of the tumor. There is interest to exploit γδ T cells in tumor immunotherapy, but to make this approach successful there is urgent need to fully understand the biological functions of γδ T cells and of how they can be manipulated in vivo and ex vivo to safely provide benefit to the host. This review focuses on our previous and ongoing studies of tumor-infiltrating γδ T lymphocytes in different types of human cancer. Moreover, we discuss the interaction of tumor-infiltrating γδ T cells with other cells and molecules present in the tumor microenvironment, and their clinical relevance on the ground, that deep knowledge in this field can be used further for better immunotherapeutic intervention in cancer.

7.
J Leukoc Biol ; 108(2): 749-760, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32202356

RESUMO

Inflammatory bowel disease (IBD) remains a global health problem with a significant percentage of patients progressing to chronic inflammation and colitis-associated cancer (CAC). Whether or not γδ T cells contribute to initiation and maintenance of inflammation in IBD and in the development of CAC is not known. We have evaluated the frequency, phenotype, and functions of γδ T cells among tissue-infiltrating lymphocytes in healthy donors and IBD and CAC patients. Results show that Vδ1 T cells are the dominant γδ T-cell population in healthy tissue, whereas Vδ2 T significantly abound in chronic IBD. Vδ2 T cells produce more IFN-γ, TNF-α, and IL-17 than Vδ1 T cells in chronic inflamed IBD. In CAC patients no significant cytokine production was detected in tissue-resident Vδ1 T cells, but Vδ2 T cells produced remarkable amounts of IFN-γ and TNF-α; these data were confirmed by the analysis of an independent cohort of IBD transcriptomes. Moreover, transcriptomes of IBD patients revealed a clear-cut clusterization of genes related with the maintenance of the inflammatory status. In conclusion, our results demonstrating that Vδ2 T cells have a proinflammatory profile in chronic IBD are suggestive of their participation in IBD and CAC pathogenesis.


Assuntos
Colite/complicações , Colite/imunologia , Neoplasias do Colo/etiologia , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto , Idoso , Biomarcadores , Doença Crônica , Colite/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Citocinas/metabolismo , Suscetibilidade a Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Imunofenotipagem , Doenças Inflamatórias Intestinais/patologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade
8.
JCI Insight ; 4(24)2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31689241

RESUMO

γδ T cells account for a large fraction of human intestinal intraepithelial lymphocytes (IELs) endowed with potent antitumor activities. However, little is known about their origin, phenotype, and clinical relevance in colorectal cancer (CRC). To determine γδ IEL gut specificity, homing, and functions, γδ T cells were purified from human healthy blood, lymph nodes, liver, skin, and intestine, either disease-free, affected by CRC, or generated from thymic precursors. The constitutive expression of NKp46 specifically identifies a subset of cytotoxic Vδ1 T cells representing the largest fraction of gut-resident IELs. The ontogeny and gut-tropism of NKp46+/Vδ1 IELs depends both on distinctive features of Vδ1 thymic precursors and gut-environmental factors. Either the constitutive presence of NKp46 on tissue-resident Vδ1 intestinal IELs or its induced expression on IL-2/IL-15-activated Vδ1 thymocytes are associated with antitumor functions. Higher frequencies of NKp46+/Vδ1 IELs in tumor-free specimens from CRC patients correlate with a lower risk of developing metastatic III/IV disease stages. Additionally, our in vitro settings reproducing CRC tumor microenvironment inhibited the expansion of NKp46+/Vδ1 cells from activated thymic precursors. These results parallel the very low frequencies of NKp46+/Vδ1 IELs able to infiltrate CRC, thus providing insights to either follow-up cancer progression or to develop adoptive cellular therapies.


Assuntos
Neoplasias Colorretais/imunologia , Mucosa Intestinal/citologia , Linfócitos Intraepiteliais/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Linfócitos T Citotóxicos/imunologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos Ly/metabolismo , Colo/citologia , Colo/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Progressão da Doença , Feminino , Humanos , Íleo/citologia , Íleo/imunologia , Imunoterapia Adotiva/métodos , Mucosa Intestinal/imunologia , Linfócitos Intraepiteliais/metabolismo , Linfócitos Intraepiteliais/transplante , Masculino , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Globulina de Ligação a Hormônio Sexual , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/transplante , Adulto Jovem
9.
Ann Clin Lab Sci ; 49(4): 519-528, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31471343

RESUMO

OBJECTIVE: Dynamic changes of cytotoxic T cell responses against Human Immunodeficiency Virus 1 (HIV-1) infection have been the subject of an innovative investigation using antiretroviral therapy (ART). Currently, human CD8 naïve central memory (TCM), effector memory (TEM), and effector memory cells re-expressing CD45RA (TEMRA) T-cells have been thoroughly studied with ART. CD45RA is a marker usually found on naïve T-cells. MATERIALS AND METHODS: We performed a longitudinal study of mono-/polyfunctional T-cells in the peripheral blood while targeting three functionally distinct cell populations of CD4+ and CD8+ T-cells (single IL2 and IFN-γ, dual IL2/IFN-γ) in 50 HIV-1 patients. These patients consisted of 5 controllers, 15 non-controllers, 20 ART responders, and 10 highly active antiretroviral therapy (HAART) non-responders. RESULTS: We found that (1) non-controllers had the highest rate of IFN-γ-expressing CD4 or CD8, but the lowest rate of IL2-producing CD4 or CD8. (2) The control of HIV-1 infection was associated with polyfunctional Gag-specific T cell responses in controllers and responders. (3) Non-responders had high serum levels of IL2 and IFN-γ. There was a high percentage of CD4+ T cell response cells within the less differentiated phenotype in controllers. CD8+ T cell showed a high rate of TEM and TEMRA in responders. CONCLUSION: High levels of pro-inflammatory cytokines are typical in non-responders, exhausted T-cells may be associated with HIV-1 progression.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , Memória Imunológica , Antígenos Comuns de Leucócito/metabolismo , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Linfócitos T CD8-Positivos/imunologia , Citocinas/biossíntese , Citocinas/sangue , Feminino , Infecções por HIV/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
10.
Expert Opin Biol Ther ; 19(9): 887-895, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31220420

RESUMO

Introduction: Cancer immunotherapy relies on the development of an efficient and long-lasting anti-tumor response, generally mediated by cytotoxic T cells. γδ T cells possess distinctive features that justify their use in cancer immunotherapy. Areas covered: Here we will review our current knowledge on the functions of human γδ T cells that may be relevant in tumor immunity and the most recent advances in our understanding of how these functions are regulated in the tumor microenvironment. We will also discuss the major achievements and limitations of γδ T cell-based immunotherapy of cancer. Expert opinion: Several small-scale clinical trials have been conducted in cancer patients using either in vivo activation of γδ T cells or adoptive transfer of ex vivo-expanded γδ T cells. Both strategies are safe and give some clinical benefit to patients, thus providing a proof of principle for their utilization in addition to conventional therapies. However, low objective response rates have been obtained in both settings and therefore larger and well-controlled trials are needed. Discovering the factors which influence the success of γδ T cell-based immunotherapy will lead to a better understanding of their mechanism of action and to harness these cells for effective and durable anti-tumor responses.


Assuntos
Imunoterapia Adotiva , Linfócitos Intraepiteliais/imunologia , Neoplasias/terapia , Animais , Humanos , Linfócitos Intraepiteliais/transplante , Neoplasias/imunologia , Microambiente Tumoral
11.
Proc Natl Acad Sci U S A ; 116(24): 11906-11915, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31118283

RESUMO

γδ T lymphocytes represent ∼1% of human peripheral blood mononuclear cells and even more cells in most tissues of vertebrates. Although they have important anticancer functions, most current single-cell RNA sequencing (scRNA-seq) studies do not identify γδ T lymphocytes because their transcriptomes at the single-cell level are unknown. Here we show that high-resolution clustering of large scRNA-seq datasets and a combination of gene signatures allow the specific detection of human γδ T lymphocytes and identification of their T cell receptor (TCR)Vδ1 and TCRVδ2 subsets in large datasets from complex cell mixtures. In t-distributed stochastic neighbor embedding plots from blood and tumor samples, the few γδ T lymphocytes appear collectively embedded between cytotoxic CD8 T and NK cells. Their TCRVδ1 and TCRVδ2 subsets form close yet distinct subclusters, respectively neighboring NK and CD8 T cells because of expression of shared and distinct cytotoxic maturation genes. Similar pseudotime maturation trajectories of TCRVδ1 and TCRVδ2 γδ T lymphocytes were discovered, unveiling in both subsets an unattended pool of terminally differentiated effector memory cells with preserved proliferative capacity, a finding confirmed by in vitro proliferation assays. Overall, the single-cell transcriptomes of thousands of individual γδ T lymphocytes from different CMV+ and CMV- donors reflect cytotoxic maturation stages driven by the immunological history of donors. This landmark study establishes the rationale for identification, subtyping, and deep characterization of human γδ T lymphocytes in further scRNA-seq studies of complex tissues in physiological and disease conditions.


Assuntos
Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Sequência de Bases , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/fisiologia , Células Cultivadas , Humanos , Memória Imunológica/imunologia , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/imunologia , Análise de Sequência de RNA/métodos , Transcriptoma/imunologia
12.
Investig Clin Urol ; 60(2): 91-98, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30838341

RESUMO

Purpose: The aim of our study was to prospectively evaluate the distribution of gamma-delta (γδ)1 and γδ2 T cells and their phenotypes in peripheral blood and prostate samples of patients diagnosed with or without prostate cancer (PCa) at prostate biopsy. Materials and Methods: A consecutive series of 43 outpatients underwent trans-rectal echo-guided prostate biopsy for suspected PCa. Flow cytometry analysis was used to identify and characterize the γδ T cells populations in peripheral blood and tissue samples. Patients were stratified according to the presence or not of PCa, and its International Society of Urological Pathology (ISUP) grade (1 vs. ≥2). Results: The distribution of γδ T cells in peripheral blood and prostate tissue showed wide variability and non-significant differences. A slightly higher percentage of δ2 T cells and a slightly lower percentage of δ1 T cells were found in peripheral blood of cancer patients. A non-significantly higher percentage of both Vδ1 and Vδ2 was expressed in cancer tissues, but a trend for lower distribution of δ1 and δ2 T cells was observed in ISUP grade ≥2. The "central memory" and "effector memory" were the most expressed T cells phenotype in peripheral blood and tissue samples. However no substantial differences in T cells subtypes distribution between cancer and healthy tissue were observed. Conclusions: No substantially different percentages of γδ T cells were found in peripheral blood and biopsy samples of healthy and PCa patients. However a non-significant trend for lower infiltrate in higher ISUP grade cancer tissue was observed, suggesting a possible role for the immunosurveillance of PCa.


Assuntos
Linfócitos Intraepiteliais/patologia , Linfócitos do Interstício Tumoral/patologia , Células Neoplásicas Circulantes/patologia , Neoplasias da Próstata/patologia , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
13.
Ann Plast Surg ; 82(2): 245-251, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30628936

RESUMO

Hand and face transplants are becoming increasingly common, recording progressively more penile, uterus, abdominal wall, and allotransplantation cases reported worldwide. Despite current protocols allow long-term survival of the allografts, the ultimate goal of donor-specific tolerance has not been achieved yet. In fact, the harmful adverse effects related to the lifelong administration of immunosuppressive agents are the main drawbacks for vascularized composite allotransplantations. Research is very active in investigating alternative methods to induce greater tolerance while minimizing toxicity. Adipose-derived stem cells (ASCs) represent promising cell therapies for immunomodulation in preclinical and clinical settings. Their clinical appeal is due to their easy harvest in large quantities through a noninvasive and well-accepted approach; they may well promote donor-specific tolerance and potentially reduce immunosuppression. Several experimental studies exist, but lacking review articles reporting current evidence. This work proposes a literature review on the immunomodulatory role of ASCs in vascularized composite allotransplantations. In vitro and in vivo evidence will be summarized. The role that cell passaging and upstream progenitors-the so-called spheroid ASCs-may play in modulating the immune response will also be discussed. Finally, this article will summarize current knowledge on biodistribution, migration, and homing of injected stem cells. This review may well provide useful information for preclinical and clinical studies, aiming at a breakthrough for donor-specific tolerance.


Assuntos
Tecido Adiposo/imunologia , Tecido Adiposo/transplante , Sobrevivência de Enxerto/imunologia , Fatores Imunológicos/imunologia , Tolerância ao Transplante/imunologia , Alotransplante de Tecidos Compostos Vascularizados/métodos , Animais , Humanos
14.
J Crohns Colitis ; 13(7): 873-883, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-30689780

RESUMO

BACKGROUND AND AIMS: Inflammatory bowel disease [IBD] is a complex chronic inflammatory disease of the human gut with no clear aetiology. Traditionally, dysregulated adaptive immune responses play an important role even though accumulating evidence suggests a role also for innate immunity. Because of the well-known plasticity of γδ T cells, we investigated their percentage occurrence, phenotypic features and effector functions in the intestinal mucosa of early-onset and long-standing IBD patients, as compared to healthy subjects. METHODS: Fresh biopsies from 30 Crohn's disease and ulcerative colitis patients were obtained and digested, and cells were analysed by flow cytometry. RESULTS: We found a reduced frequency of Vδ1 T cells in tissue from early and late IBD patients (2.24% and 1.95%, respectively, vs 5.44% in healthy tissue) but an increased frequency of Vδ2 T cells in the gut of late IBD patients (3.19% in late patients vs 1.5% in early patients and 1.65% in healthy tissue). The infiltrating Vδ2 T cells had predominant effector memory and terminally differentiated phenotypes and produced elevated levels of tumour necrosis factor-α [TNF-α] and interleukin-17 [IL-17]. The frequency of tissue Vδ2 T cells correlated with the extent of the inflammatory response and the severity of IBD. CONCLUSION: Our study shows that tissue Vδ1 T cells are decreased in IBD patients while Vδ2 T cells are increased in the gut of IBD patients and contribute to TNF-α production. Moreover, we identify an as yet unappreciated role of Vδ2 T cells in IL-17 production in the gut of long-standing IBD patients, suggesting that they also participate in the chronic inflammatory process.


Assuntos
Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Biópsia , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
15.
Front Immunol ; 9: 1395, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29963061

RESUMO

γδ T cells possess cytotoxic antitumor activity mediated by production of proinflammatory cytokines, direct cytotoxic activity, and regulation of the biological functions of other cell types. Hence, these features have prompted the development of therapeutic strategies in which γδ T cells agonists or ex vivo-expanded γδ T cells are administered to tumor patients. Several studies have shown that γδ T cells are an important component of tumor-infiltrating lymphocytes in patients affected by different types of cancer and a recent analysis of ~18,000 transcriptomes from 39 human tumors identified tumor-infiltrating γδ T cells as the most significant favorable cancer-wide prognostic signature. However, the complex and intricate interactions between tumor cells, tumor microenvironment (TME), and tumor-infiltrating immune cells results in a balance between tumor-promoting and tumor-controlling effects, and γδ T cells functions are often diverted or impaired by immunosuppressive signals originating from the TME. This review focuses on the dangerous liason between γδ T cells and tumoral microenvironment and raises the possibility that strategies capable to reduce the immunosuppressive environment and increase the cytotoxic ability of γδ T cells may be the key factor to improve their utilization in tumor immunotherapy.

16.
J Leukoc Biol ; 103(3): 485-492, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29345336

RESUMO

γδ T cells are a subset of T lymphocytes that have been implicated in immunosurveillance against infections and tumors. γδ T cells are endowed with antitumor activities, and hence several γδ T cell-based small-scale clinical trials have been conducted either by in vivo activation by intravenous administration of aminobiphosphonates or by adoptive transfer of in vitro expanded γδ T cells. Although both these strategies have yielded promising results, there are a number of limitations associated with each of them which, if overcome may help to further improve efficacy. One of the most important limits is the possible polarization of tumor-infiltrating γδ T cells toward different γδ T cells population with functional activities that help the progression and spread of the tumor. Here, we review the modalities and the possible mechanisms involved in the polarization of tumor-infiltrating γδ T cells upon interaction with several components of the tumor microenvironment and discuss their implications for the manipulation of γδ T cells in cancer immunotherapy.


Assuntos
Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo
18.
Front Immunol ; 8: 1401, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29163482

RESUMO

γδ T cells are a minor population (~5%) of CD3 T cells in the peripheral blood, but abound in other anatomic sites such as the intestine or the skin. There are two major subsets of γδ T cells: those that express Vδ1 gene, paired with different Vγ elements, abound in the intestine and the skin, and recognize the major histocompatibility complex (MHC) class I-related molecules such as MHC class I-related molecule A, MHC class I-related molecule B, and UL16-binding protein expressed on many stressed and tumor cells. Conversely, γδ T cells expressing the Vδ2 gene paired with the Vγ9 chain are the predominant (50-90%) γδ T cell population in the peripheral blood and recognize phosphoantigens (PAgs) derived from the mevalonate pathway of mammalian cells, which is highly active upon infection or tumor transformation. Aminobisphosphonates (n-BPs), which inhibit farnesyl pyrophosphate synthase, a downstream enzyme of the mevalonate pathway, cause accumulation of upstream PAgs and therefore promote γδ T cell activation. γδ T cells have distinctive features that justify their utilization in antitumor immunotherapy: they do not require MHC restriction and are less dependent that αß T cells on co-stimulatory signals, produce cytokines with known antitumor effects as interferon-γ and tumor necrosis factor-α and display cytotoxic and antitumor activities in vitro and in mouse models in vivo. Thus, there is interest in the potential application of γδ T cells in tumor immunotherapy, and several small-sized clinical trials have been conducted of γδ T cell-based immunotherapy in different types of cancer after the application of PAgs or n-BPs plus interleukin-2 in vivo or after adoptive transfer of ex vivo-expanded γδ T cells, particularly the Vγ9Vδ2 subset. Results from clinical trials testing the efficacy of any of these two strategies have shown that γδ T cell-based therapy is safe, but long-term clinical results to date are inconsistent. In this review, we will discuss the major achievements and pitfalls of the γδ T cell-based immunotherapy of cancer.

19.
Cancer Res ; 77(12): 3268-3279, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28400477

RESUMO

The tumor microenvironment supplies proinflammatory cytokines favoring a permissive milieu for cancer cell growth and invasive behavior. Here we show how breast cancer progression is facilitated by IL4 secreted by adipose tissue and estrogen receptor-positive and triple-negative breast cancer cell types. Blocking autocrine and paracrine IL4 signaling with the IL4Rα antagonist IL4DM compromised breast cancer cell proliferation, invasion, and tumor growth by downregulating MAPK pathway activity. IL4DM reduced numbers of CD44+/CD24- cancer stem-like cells and elevated expression of the dual specificity phosphatase DUSP4 by inhibiting NF-κB. Enforced expression of DUSP4 drove conversion of metastatic cells to nonmetastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4 activated the ERK and p38 MAPK pathways, increased stem-like properties, and spawned metastatic capacity. Targeting IL4 signaling sensitized breast cancer cells to anticancer therapy and strengthened immune responses by enhancing the number of IFNγ-positive CTLs. Our results showed the role of IL4 in promoting breast cancer aggressiveness and how its targeting may improve the efficacy of current therapies. Cancer Res; 77(12); 3268-79. ©2017 AACR.


Assuntos
Neoplasias da Mama/patologia , Fosfatases de Especificidade Dupla/metabolismo , Interleucina-4/metabolismo , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Microambiente Tumoral , Western Blotting , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Citometria de Fluxo , Xenoenxertos , Humanos
20.
Cancer Immunol Res ; 5(5): 397-407, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28351891

RESUMO

The identification of reciprocal interactions between tumor-infiltrating immune cells and the microenviroment may help us understand mechanisms of tumor growth inhibition or progression. We have assessed the frequencies of tumor-infiltrating and circulating γδ T cells and regulatory T cells (Treg) from 47 patients with squamous cell carcinoma (SCC), to determine if they correlated with progression or survival. Vδ1 T cells infiltrated SSC tissue to a greater extent than normal skin, but SCC patients and healthy subjects had similar amounts circulating. However, Vδ2 T cells were present at higher frequencies in circulation than in the tissue of either cancer patients or healthy donors. Tregs were decreased in the peripheral blood of SCC patients, but were significantly increased in the tumor compartment of these patients. Tumor-infiltrating γδ T cells preferentially showed an effector memory phenotype and made either IL17 or IFNγ depending on the tumor stage, whereas circulating γδ T cells of SCC patients preferentially made IFNγ. Different cell types in the tumor microenvironment produced chemokines that could recruit circulating γδ T cells to the tumor site and other cytokines that could reprogram γδ T cells to produce IL17. These findings suggest the possibility that γδ T cells in SCC are recruited from the periphery and their features are then affected by the tumor microenvironment. Elevated frequencies of infiltrating Vδ2 T cells and Tregs differently correlated with early and advanced tumor stages, respectively. Our results provide insights into the functions of tumor-infiltrating γδ T cells and define potential tools for tumor immunotherapy. Cancer Immunol Res; 5(5); 397-407. ©2017 AACR.


Assuntos
Carcinoma de Células Escamosas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Cutâneas/imunologia , Subpopulações de Linfócitos T/imunologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Citocinas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Cutâneas/patologia , Microambiente Tumoral
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