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1.
Eur J Immunol ; 51(4): 879-892, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33368232

RESUMEN

Mucosal associated invariant T (MAIT) cells are anti-microbial innate-like T cells that are abundant in blood and liver. MAIT cells express a semi-invariant T-cell receptor (TCR) that recognizes a pyrimidine ligand, derived from microbial riboflavin synthesis, bound to MR1. Both blood and liver derived (ld)-MAIT cells can be robustly stimulated via TCR or by cytokines produced during bacterial or viral infection. In this study, we compared the functional and transcriptomic response of human blood and ld-MAIT cells to TCR signals (Escherichia coli or the pyrimidine ligand) and cytokines (IL-12 + IL-18). While the response of blood and ld-MAIT cells to TCR signals were comparable, following cytokine stimulation ld-MAIT cells were more polyfunctional than blood MAIT cells. Transcriptomic analysis demonstrated different effector programmes of ld-MAIT cells with the two modes of activation, including the enrichment of a tissue repair signature in TCR-stimulated MAIT cells. Interestingly, we observed enhancement of IL-12 signaling and fatty acid metabolism in untreated ld-MAIT cells compared with blood MAIT cells. Additionally, MAIT cells from blood and liver were modulated similarly by TCR and cytokine signals. Therefore, we report that blood and ld-MAIT cells are fundamentally different but undergo conserved changes following activation via TCR or by cytokines.


Asunto(s)
Hígado/inmunología , Activación de Linfocitos/inmunología , Células T Invariantes Asociadas a Mucosa/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Análisis de Varianza , Recolección de Muestras de Sangre/métodos , Células Cultivadas , Citocinas/genética , Citocinas/inmunología , Citocinas/metabolismo , Perfilación de la Expresión Génica/métodos , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Hígado/citología , Activación de Linfocitos/genética , Células T Invariantes Asociadas a Mucosa/citología , Células T Invariantes Asociadas a Mucosa/metabolismo , RNA-Seq/métodos , Receptores de Antígenos de Linfocitos T/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transcriptoma/genética , Transcriptoma/inmunología
2.
Scand J Med Sci Sports ; 32(5): 856-865, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35088469

RESUMEN

PURPOSE: Improving cardiopulmonary reserve, or peak oxygen consumption( V ˙ O2peak ), may reduce postoperative complications; however, this may be difficult to achieve between diagnosis and surgery. Our primary aim was to assess the efficacy of an approximate 14-session, preoperative high-intensity interval training(HIIT) program to increase V ˙ O2peak by a clinically relevant 2 ml·kg-1 ·min-1 . Our secondary aim was to document clinical outcomes. METHODOLOGY: In this prospective study, participants aged 45-85 undergoing major abdominal surgery were randomized to standard care or 14 sessions of HIIT over 4 weeks. HIIT sessions involved approximately 30 min of stationary cycling. Interval training alternated 1 min of high (with the goal of reaching 90% max heart rate at least once during the session) and low/moderate-intensity cycling. Cardiopulmonary exercise testing(CPET) measured the change in V ˙ O2peak from baseline to surgery. Clinical outcomes included postoperative complications, length of stay(LOS), and Short Form 36 quality of life questionnaire(SF-36). RESULTS: Of 63 participants, 46 completed both CPETs and 50 completed clinical follow-up. There was a significant improvement in the HIIT group's mean ± SD V ˙ O2peak (HIIT 2.87 ± 1.94 ml·kg1 ·min-1 vs standard care 0.15 ± 1.93, with an overall difference of 2.73 ml·kg1 ·min-1 95%CI [1.53, 3.93] p < 0.001). There were no statistically significant differences between groups for clinical outcomes, although the observed differences consistently favored the exercise group. This was most notable for total number of complications (0.64 v 1.16 per patient, p = 0.07), SF-36 physical component score (p = 0.06), and LOS (mean 5.5 v 7.4 days, p = 0.07). CONCLUSIONS: There was a significant improvement in V ˙ O2peak with a four-week preoperative HIIT program. Further appropriately powered work is required to explore the impact of preoperative HIIT on postoperative clinical outcomes.


Asunto(s)
Entrenamiento de Intervalos de Alta Intensidad , Prueba de Esfuerzo , Humanos , Consumo de Oxígeno , Complicaciones Posoperatorias/prevención & control , Estudios Prospectivos , Calidad de Vida
3.
Eur J Immunol ; 50(2): 178-191, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31608441

RESUMEN

Mucosal associated invariant T (MAIT) cells are abundant unconventional T cells that can be stimulated either via their TCR or by innate cytokines. The MAIT cell TCR recognises a pyrimidine ligand, derived from riboflavin synthesising bacteria, bound to MR1. In infection, bacteria not only provide the pyrimidine ligand but also co-stimulatory signals, such as TLR agonists, that can modulate TCR-mediated activation. Recently, type I interferons (T1-IFNs) have been identified as contributing to cytokine-mediated MAIT cell activation. However, it is unknown whether T1-IFNs also have a role during TCR-mediated MAIT cell activation. In this study, we investigated the co-stimulatory role of T1-IFNs during TCR-mediated activation of MAIT cells by the MR1 ligand 5-amino-6-d-ribitylaminouracil/methylglyoxal. We found that T1-IFNs were able to boost interferon-γ and granzyme B production in 5-amino-6-d-ribitylaminouracil/methylglyoxal-stimulated MAIT cells. Similarly, influenza virus-induced T1-IFNs enhanced TCR-mediated MAIT cell activation. An essential role of T1-IFNs in regulating MAIT cell activation by riboflavin synthesising bacteria was also demonstrated. The co-stimulatory role of T1-IFNs was also evident in liver-derived MAIT cells. T1-IFNs acted directly on MAIT cells to enhance their response to TCR stimulation. Overall, our findings establish an important immunomodulatory role of T1-IFNs during TCR-mediated MAIT cell activation.


Asunto(s)
Interferón Tipo I/inmunología , Células T Invariantes Asociadas a Mucosa/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Células Cultivadas , Citocinas/inmunología , Humanos , Inmunidad Innata/inmunología , Interferón gamma/inmunología , Ligandos , Activación de Linfocitos/inmunología
4.
J Immunol ; 202(6): 1871-1884, 2019 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-30728210

RESUMEN

T cell infiltration of tumors plays an important role in determining colorectal cancer disease progression and has been incorporated into the Immunoscore prognostic tool. In this study, mass cytometry was used to demonstrate a significant increase in the frequency of both conventional CD25+FOXP3+CD127lo regulatory T cells (Tregs) as well as BLIMP-1+ Tregs in the tumor compared with nontumor bowel (NTB) of the same patients. Network cluster analyses using SCAFFoLD, VorteX, and CITRUS revealed that an increase in BLIMP-1+ Tregs was a single distinguishing feature of the tumor tissue compared with NTB. BLIMP-1+ Tregs represented the most significantly enriched T cell population in the tumor compared with NTB. The enrichment of ICOS, CD45RO, PD-1, PDL-1, LAG-3, CTLA-4, and TIM-3 on BLIMP-1+ Tregs suggests that BLIMP-1+ Tregs have a more activated phenotype than conventional Tregs and may play a role in antitumor immune responses.


Asunto(s)
Separación Celular/métodos , Neoplasias Colorrectales/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Anciano , Femenino , Humanos , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad
5.
Int J Cancer ; 143(8): 2008-2016, 2018 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-29752720

RESUMEN

Tumor infiltrating T cells are a predictor of patient outcome in patients with colorectal cancer (CRC). However, many T cell populations have been associated with both poor and positive patient prognoses, indicating a need to further understand the role of different T cell subsets in CRC. In this study, the T cell infiltrate from the tumor and nontumor bowel (NTB) was examined in 95 CRC patients using flow cytometry and associations with cancer stage and disease recurrence made. Our findings showed that IFN-γ-producing T cells were associated with positive patient outcomes, and CD69+ T cells were associated with disease recurrence. Inflammatory (IL-17) and regulatory T cells were not associated with disease recurrence. Surprisingly, in a second cohort of 32 patients with long-term clinical follow up data, tumor infiltrating IL-2-producing T cells correlated negatively with disease free survival (DFS) and a higher frequency of IL-2-producing T cells was found in the NTB of patients with poorly differentiated tumors. These results point toward the possibility of a negative impact of IL-2 in tumor immune responses, which may influence future immunotherapy treatments in CRC patients.


Asunto(s)
Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Interleucina-2/metabolismo , Lectinas Tipo C/metabolismo , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patología , Anciano , Diferenciación Celular/fisiología , Supervivencia sin Enfermedad , Femenino , Humanos , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Masculino , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias/métodos , Pronóstico
6.
Cancer Immunol Immunother ; 66(4): 515-522, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28116480

RESUMEN

Analysis of tumour-infiltrating T cells in colorectal cancer can predict disease-free survival. The Immunoscore, obtained by quantifying tumour-infiltrating CD3+ and CD8+ T cells, may improve current staging. Effector regulatory T cells are a potently suppressive subset in mice and, while present in human colorectal cancer, their role in patient outcome is unknown. Immunofluorescence was used to analyse immune cell infiltrates in patients with early (stage II) colorectal cancer with (n = 13) and without (n = 19) recurrent disease. CD3 and CD8 were used for the Immunoscore; FOXP3, BLIMP-1 and CD3 to identify effector regulatory T cells. Patients with high Immunoscores had increased disease-free survival compared to patients with low Immunoscores (Log-rank test p < 0.01). Prediction of outcome was further improved by stratifying patients with a low Immunoscore according to CD3+FOXP3+BLIMP-1+ cell infiltration at the invasive margin. Patients with a low Immunoscore and high infiltrate of CD3+FOXP3+BLIMP-1+ cells tended to have better disease-free survival than patients with low Immunoscore and low infiltrate of CD3+FOXP3+BLIMP-1+ cells. Patients with a high Immunoscore had better disease-free survival than patients with a low Immunoscore and low infiltrate of CD3+ FOXP3+ BLIMP-1+ cells (Log-rank test p < 0.001). These results indicate that tumour infiltration with effector regulatory T cells improves the prognostic value of the Immunoscore and implies that these cells may play a role in colorectal cancer patient outcome.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Neoplasias Colorrectales/diagnóstico , Linfocitos Infiltrantes de Tumor/inmunología , Proteínas Represoras/metabolismo , Linfocitos T Reguladores/inmunología , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Pruebas Inmunológicas , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Nueva Zelanda , Proyectos Piloto , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Valor Predictivo de las Pruebas , Pronóstico , Análisis de Supervivencia
7.
Methods Mol Biol ; 2588: 231-248, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36418692

RESUMEN

Circulating tumor cells (CTCs) are precursors of the metastatic cascade, which is responsible for 90% of all cancer-related deaths. CTCs arise from solid tumors and travel through the bloodstream and lymphatic system. Developments in the isolation and analysis of CTCs promise potential biomarker assays for detection and monitoring of cancer through a minimally invasive procedure. Despite this, the precise role of CTCs in metastasis remains poorly characterized, mainly due to the low density of CTCs (1-10 CTCs per 10 mL of blood) present in patient blood and the lack of robust methods for their isolation in a standard laboratory setting. CellSearch is currently the only FDA-approved CTC enrichment protocol, but limitations of this EpCAM-based method include cost, availability, and the use of a single surface marker for capture. To address these limitations, we have optimized an existing method, MetaCell, which exploits the differences in size of CTCs compared to other blood cells for CTC enrichment from blood. MetaCell contains a membrane with 8 µm pores, and blood is filtered through this kit by capillary action and CTCs, which are typically larger than the pores and remain on top of the membrane, while most leukocytes pass through the pores. The membrane along with these CTCs can be detached and transferred to 6-well plates for culturing or directly used for characterization. Here, we provide a detailed protocol for enrichment of CTCs using the filtration device MetaCell and a procedure for characterization of CTCs by immunohistochemical staining.


Asunto(s)
Neoplasias Colorrectales , Células Neoplásicas Circulantes , Humanos , Recuento de Células , Leucocitos , Filtración
8.
Cancers (Basel) ; 14(14)2022 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-35884509

RESUMEN

Circulating tumour cells (CTC) from solid tumours are a prerequisite for metastasis. Isolating CTCs and understanding their biology is essential for developing new clinical tests and precision oncology. Currently, CellSearch is the only FDA (U.S. Food and Drug Administration)-approved method for CTC enrichment but possesses several drawbacks owing to a reliance on the epithelial cell adhesion molecule (EpCAM) and a resource-intensive nature. Addressing these shortcomings, we optimised an existing size-based method, MetaCell, to enrich CTCs from blood of colorectal cancer (CRC) patients. We evaluated the ability of MetaCell to enrich CTCs by spiking blood with CRC cell lines and assessing the cell recovery rates and WBC depletion via immunostaining and gene expression. We then applied MetaCell to samples from 17 CRC patients and seven controls. Recovery rates were >85% in cell lines, with >95% depletion in WBCs. MetaCell yielded CTCs and CTC clusters in 52.9% and 23.5% of the patients, respectively, without false positives in control patients. CTCs and cluster detection did not correlate with histopathological parameters. Overall, we demonstrated that the MetaCell platform enriched CRC cells with high recovery rates and high purity. Our pilot study also demonstrated the ability of MetaCell to detect CTCs in CRC patients.

9.
JNCI Cancer Spectr ; 6(6)2022 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-36255250

RESUMEN

Genomic analysis of tumors is transforming our understanding of cancer. However, although a great deal of attention is paid to the accuracy of the cancer genomic data itself, less attention has been paid to the accuracy of the associated clinical information that renders the genomic data useful for research. In this brief communication, we suggest that omissions and errors in clinical annotations have a major impact on the interpretation of cancer genomic data. We describe our discovery of annotation omissions and errors when reviewing an already carefully annotated colorectal cancer gene expression dataset from our laboratory. The potential importance of clinical annotation omissions and errors was then explored using simulation analyses with an independent genomic dataset. We suggest that the completeness and veracity of clinical annotations accompanying cancer genomic data require renewed focus by the oncology research community, when planning new collections and when interpreting existing cancer genomic data.


Asunto(s)
Genómica , Neoplasias , Humanos , Simulación por Computador , Neoplasias/genética
10.
Trials ; 19(1): 331, 2018 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-29941028

RESUMEN

BACKGROUND: Risk factors, such as the number of pre-existing co-morbidities, the extent of the underlying pathology and the magnitude of the required operation, cannot be changed before surgery. It may, however, be possible to improve the cardiopulmonary fitness of the patient with an individualised exercise program. We are performing a randomised controlled trial (RCT) assessing the impact of High Intensity Interval Training (HIIT) on preoperative cardiopulmonary fitness and postoperative outcomes in patients undergoing major abdominal surgery. METHODS: Consecutive eligible patients undergoing elective abdominal surgery are being randomised to HIIT or standard care in a 1:1 ratio. Participants allocated to HIIT will perform 14 exercise sessions on a stationary cycle ergometer, over a period of 4-6 weeks before surgery. The sessions, which are individualised, aim to start with ten repeated 1-min blocks of intense exercise with a target of reaching a heart rate exceeding 90% of the age predicted maximum, followed by 1 min of lower intensity cycling. As endurance improves, the duration of exercise is increased to achieve five 2-min intervals of high intensity exercise followed by 2 min of lower intensity cycling. Each training session lasts approximately 30 min. The primary endpoint, change in peak oxygen consumption (Peak VO2) measured during cardiopulmonary exercise testing, is assessed at baseline and before surgery. Secondary endpoints include postoperative complications, length of hospital stay and three clinically validated scores: the surgical recovery scale; the postoperative morbidity survey; and the SF-36 quality of life score. The standard deviation for changes in Peak VO2 will be assessed after the first 30 patients and will be used to calculate the required sample size. DISCUSSION: We want to assess if 14 sessions of HIIT is sufficient to improve Peak VO2 by 2 mL/kg/min in patients undergoing major abdominal surgery and to explore the best clinical endpoint for a subsequent RCT designed to assess if improving Peak VO2 will translate into improving clinical outcomes after surgery. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12617000587303 . Registered on 26 April 2017.


Asunto(s)
Abdomen/cirugía , Capacidad Cardiovascular , Entrenamiento de Intervalos de Alta Intensidad , Cuidados Preoperatorios/métodos , Anciano , Anciano de 80 o más Años , Ciclismo , Procedimientos Quirúrgicos Electivos , Tolerancia al Ejercicio , Femenino , Estado de Salud , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Nueva Zelanda , Consumo de Oxígeno , Complicaciones Posoperatorias/etiología , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Recuperación de la Función , Factores de Tiempo , Resultado del Tratamiento
11.
Nat Commun ; 9(1): 254, 2018 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-29343721

RESUMEN

∆122p53 mice (a model of ∆133p53 isoform) are tumour-prone, have extensive inflammation and elevated serum IL-6. To investigate the role of IL-6 we crossed ∆122p53 mice with IL-6 null mice. Here we show that loss of IL-6 reduced JAK-STAT signalling, tumour incidence and metastasis. We also show that ∆122p53 activates RhoA-ROCK signalling leading to tumour cell invasion, which is IL-6-dependent and can be reduced by inhibition of JAK-STAT and RhoA-ROCK pathways. Similarly, we show that Δ133p53 activates these pathways, resulting in invasive and migratory phenotypes in colorectal cancer cells. Gene expression analysis of colorectal tumours showed enrichment of GPCR signalling associated with ∆133TP53 mRNA. Patients with elevated ∆133TP53 mRNA levels had a shorter disease-free survival. Our results suggest that ∆133p53 promotes tumour invasion by activation of the JAK-STAT and RhoA-ROCK pathways, and that patients whose tumours have high ∆133TP53 may benefit from therapies targeting these pathways.


Asunto(s)
Neoplasias Colorrectales/metabolismo , Interleucina-6/metabolismo , Quinasas Janus/metabolismo , Factores de Transcripción STAT/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Animales , Línea Celular Tumoral , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Femenino , Células HCT116 , Humanos , Masculino , Ratones , Invasividad Neoplásica , Metástasis de la Neoplasia , Pronóstico , Isoformas de Proteínas , ARN Mensajero/metabolismo , Transducción de Señal
12.
Oncoimmunology ; 5(11): e1234573, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27999752

RESUMEN

T cells play a crucial role in preventing the growth and spread of colorectal cancer (CRC). However, immunotherapies against CRC have only shown limited success, which may be due to lack of understanding about the effect of the local tumor microenvironment (TME) on T cell function. The goal of this study was to determine whether T cells in tumor tissue were functionally impaired compared to T cells in non-tumor bowel (NTB) tissue from the same patients. We showed that T cell populations are affected differently by the TME. In the tumor, T cells produced more IL-17 and less IL-2 per cell than their counterparts from NTB tissue. T cells from tumor tissue also had impaired proliferative ability compared to T cells in NTB tissue. This impairment was not related to the frequency of IL-2 producing T cells or regulatory T cells, but T cells from the TME had a higher co-expression of inhibitory receptors than T cells from NTB. Overall, our data indicate that T cells in tumor tissue are functionally altered by the CRC TME, which is likely due to cell intrinsic factors. The TME is therefore an important consideration in predicting the effect of immune modulatory therapies.

13.
Clin Transl Immunology ; 5(4): e76, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27195119

RESUMEN

In contrast to many cancers, a high infiltration of macrophages in colorectal cancer (CRC) has been associated with improved prognosis for patients. Cytokines and other stimuli from the tumor microenvironment affect monocyte to macrophage maturation and subsequent phenotype and function. Heterogeneous myeloid populations were identified using a novel flow cytometry panel in both tumor and paired non-tumor bowel (NTB) from CRC patients. The frequency of macrophage subsets with a gut-conditioned phenotype was lower in tumor compared with NTB. We used an in vitro system to show that two of the macrophage populations represented pro-inflammatory and anti-inflammatory phenotypes. Conditioned media that contained high levels of interleukin-6 promoted and maintained an anti-inflammatory phenotype in vitro. This study demonstrates the plasticity and heterogeneity of macrophage subtypes in human CRC, and the feasibility of studying complex populations. Ex vivo experiments demonstrate that macrophage subsets are influenced by the tumor microenvironment.

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