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1.
Cancer Sci ; 111(3): 817-825, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31925976

RESUMEN

Recent studies have reported that tumor-infiltrating mast cells (TIM) play an important role in tumor regression, but the effect of TIM in gallbladder cancer (GBC) remains unclear. The present study aims to investigate the prognostic value of TIM in GBC patients and its responsiveness to gemcitabine-based adjuvant chemotherapy (ACT). A total of 298 GBC patients from Zhongshan Hospital were recruited for this study. TIM infiltration was measured by immunohistochemical staining. Accumulation of TIM is significantly associated with prolonged overall survival in GBC patients. The benefit from gemcitabine-based ACT was superior among patients with high infiltration of TIM with GBC. Multivariate analysis identified TIM infiltration as an independent prognostic factor for overall survival. A heatmap showed that TIM-activated gene signatures were positively correlated with CD8+ T cells' gene signatures. Gene set enrichment analysis (GSEA) suggested that TIM was related to multiple T cell-related processes and signaling pathways, including the interferon gamma signaling pathway and the leukocyte migration signaling pathway. It was confirmed that CD8+ T cell infiltration was positively correlated with high TIM infiltration in tissue microarray (TMA), suggesting that TIM infiltration was linked to the immune surveillance in GBC. TIM can be used as an independent prognostic factor and a predictor of therapeutic response of gemcitabine-based ACT in GBC patients, which may mediate immune surveillance by recruiting and activating CD8+ T cells in GBC.


Asunto(s)
Neoplasias de la Vesícula Biliar/patología , Linfocitos Infiltrantes de Tumor/patología , Mastocitos/patología , Antimetabolitos Antineoplásicos/uso terapéutico , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Quimioterapia Adyuvante/métodos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Femenino , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Neoplasias de la Vesícula Biliar/metabolismo , Humanos , Interferón gamma/metabolismo , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Persona de Mediana Edad , Pronóstico , Transducción de Señal/efectos de los fármacos
2.
Am J Forensic Med Pathol ; 41(1): 32-34, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32000220

RESUMEN

Thymus glands from 283 autopsy cases were sampled and evaluated with histochemical and immunohistochemical methods. A subpopulation of 41 intravenous drug addicts were compared with age-matched control cases.It was found that an accelerated involution of the thymus occurred in the 20- to 25-year interval and thereafter with a steady pace of 5% per year. Also the size of Hassall bodies declined successively.In drug addicts, an increased dystrophic calcification of the Hassall bodies and a significant difference in thymus size (atrophy) compared with controls were seen. Moreover, a difference was seen in the relative numbers of CD4 and CD8 lymphocytes where CD4+ cells were reduced in drug addicts.It is hypothesized that signs of hepatitis C virus infection that was found in the majority of drug addicts and the reduced number of functionally intact Hassall corpuscles could explain the reduction of CD4+ lymphocytes and thymic hypotrophy in this population.


Asunto(s)
Consumidores de Drogas , Abuso de Sustancias por Vía Intravenosa , Timo/patología , Adolescente , Adulto , Envejecimiento/patología , Atrofia/patología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/patología , Calcinosis/patología , Estudios de Casos y Controles , Femenino , Patologia Forense , Hepatitis C Crónica/patología , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
3.
Cancer Immunol Immunother ; 69(1): 81-94, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31844909

RESUMEN

Amino acid deprivation is a strategy that malignancies utilize to blunt anti-tumor T-cell immune responses. It has been proposed that amino acid insufficiency in T-cells is detected by GCN2 kinase, which through phosphorylation of EIF2α, shuts down global protein synthesis leading to T-cell arrest. The role of this amino acid stress sensor in the context of malignant brain tumors has not yet been studied, and may elucidate important insights into the mechanisms of T-cell survival in this harsh environment. Using animal models of glioblastoma and animals with deficiency in GCN2, we explored the importance of this pathway in T-cell function within brain tumors. Our results show that GCN2 deficiency limited CD8+ T-cell activation and expression of cytotoxic markers in two separate murine models of glioblastoma in vivo. Importantly, adoptive transfer of antigen-specific T-cells from GCN2 KO mice did not control tumor burden as well as wild-type CD8+ T-cells. Our in vitro and in vivo data demonstrated that reduction in amino acid availability caused GCN2 deficient CD8+ T-cells to become rapidly necrotic. Mechanistically, reduced CD8+ T-cell activation and necrosis was due to a disruption in TCR signaling, as we observed reductions in PKCθ and phoshpo-PKCθ on CD8+ T-cells from GCN2 KO mice in the absence of tryptophan. Validating these observations, treatment of wild-type CD8+ T-cells with a downstream inhibitor of GCN2 activation also triggered necrosis of CD8+ T-cells in the absence of tryptophan. In conclusion, our data demonstrate the vital importance of intact GCN2 signaling on CD8+ T-cell function and survival in glioblastoma.


Asunto(s)
Neoplasias Encefálicas/inmunología , Linfocitos T CD8-positivos/inmunología , Glioblastoma/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Escape del Tumor/inmunología , Traslado Adoptivo , Animales , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/trasplante , Línea Celular Tumoral/trasplante , Supervivencia Celular/inmunología , Modelos Animales de Enfermedad , Glioblastoma/patología , Glioblastoma/terapia , Humanos , Activación de Linfocitos , Ratones , Ratones Noqueados , Necrosis/genética , Necrosis/inmunología , Fosforilación/inmunología , Biosíntesis de Proteínas/inmunología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/inmunología
4.
Nat Med ; 25(10): 1549-1559, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31591606

RESUMEN

Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ubiquitous and regional TCRs correlates with the number of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs form part of clusters of TCRs of similar sequence, suggestive of a spatially constrained antigen-driven process. CD8+ tumor-infiltrating lymphocytes harboring ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous TCRs are preferentially detected in the blood at the time of tumor resection as compared to routine follow-up. These findings highlight a noninvasive method to identify and track relevant tumor-reactive TCRs for use in adoptive T cell immunotherapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Heterogeneidad Genética , Inmunoterapia Adoptiva , Receptores de Antígenos de Linfocitos T/genética , Anciano , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Mutación , Receptores de Antígenos de Linfocitos T/inmunología
5.
Immunology ; 158(2): 136-149, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31515801

RESUMEN

Immune-checkpoint blockade antibodies have been approved for the treatment of cancer. However, poorly immunogenic tumours are less responsive to such therapies. Agonistic anti-Toll-like receptor 4 (TLR4) monoclonal antibodies (mAbs) activate only cell-surface TLR4; in contrast, lipopolysaccharide (LPS) activates both TLR4 and intracellular inflammatory caspases. In this study, we investigated the adjuvant activity of an anti-TLR4 mAb in T-cell-mediated antitumour immunity. The anti-TLR4 mAb induced the activation of antigen-specific T-cells in adoptive transfer studies. The growth of ovalbumin (OVA)-expressing tumours was significantly suppressed by administration of OVA and the anti-TLR4 mAb in combination, but not individually. The antitumour effect of anti-PD-1 mAb was enhanced in mice administered with OVA plus the anti-TLR4 mAb. The OVA-specific IFN-γ-producing CD8 T-cells were induced by administration of OVA and the anti-TLR4 mAb. The suppression of tumour growth was diminished by depletion of CD8, but not CD4, T-cells. The inflammatory response to the anti-TLR4 mAb was of significantly lesser magnitude than that to LPS, as assessed by NF-κB activation and production of TNF-α, IL-6 and IL-1ß. Administration of LPS (at a dose that elicited levels of proinflammatory cytokines comparable to those by the anti-TLR4 mAb) plus OVA induced no or less-marked activation of OVA-specific T-cells and failed to suppress tumour growth in mice. In conclusion, the agonistic anti-TLR4 mAb induces potent CD8 T-cell-dependent antitumour immunity and an inflammatory response of lesser magnitude than does LPS. The agonistic anti-TLR4 mAb has potential as an adjuvant for use in vaccines against cancer.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Anticuerpos Monoclonales/farmacología , Antineoplásicos Inmunológicos/farmacología , Melanoma Experimental/terapia , Neoplasias Cutáneas/terapia , Receptor Toll-Like 4/antagonistas & inhibidores , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Inmunización , Inmunoterapia/métodos , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Lipopolisacáridos/farmacología , Activación de Linfocitos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , FN-kappa B/genética , FN-kappa B/inmunología , Ovalbúmina/administración & dosificación , Cultivo Primario de Células , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/patología , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología
6.
J Cancer Res Clin Oncol ; 145(12): 3105-3114, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31562550

RESUMEN

PURPOSE: Tumor inflammatory response was evaluated as a prognostic feature in triple-negative breast cancer (TNBC) and compared with the clinical prognosticators of breast cancer and selected biomarkers of cancer cell proliferation. METHODS: TNBC patients (n = 179) with complete clinical data and up to 18-year follow-up were obtained from Auria biobank, Turku University Hospital, Turku, Finland. Tumor-infiltrating lymphocytes (TILs) and several subtypes of inflammatory cells detected with immunohistochemistry were evaluated in different tumor compartments in full tissue sections and tissue microarrays. RESULTS: Deficiency of stromal TILs and low number of CD8+ T cells independently predicted mortality in TNBC (HR 2.4, p 0.02 and HR 2.1, p 0.02, respectively). Each 10% decrease in stromal TILs resulted in 20% increased risk of mortality. An average of 13.2-year survival difference was observed between the majority (> 75%) of patients with low (< 14% of TILs) vs high (≥ 14% of TILs) frequency of CD8+ T cells. The prognostic value of TILs and CD8+ T cells varied when evaluated in different tumor compartments. TILs and CD8+ T cells were significantly associated with Securin and Separase, essential regulators of metaphase-anaphase transition of the cell cycle. DISCUSSION: TILs and CD8+ T cells provide additional prognostic value to the established clinical prognostic markers in TNBC. However, possible clinical applications would still benefit from systematic guidelines for evaluating tumor inflammatory response. Increasing understanding on the interactions between the regulation of cancer cell proliferation and inflammatory response may in future advance treatment of TNBC.


Asunto(s)
Linfocitos T CD8-positivos/patología , Linfocitos Infiltrantes de Tumor/patología , Neoplasias de la Mama Triple Negativas/patología , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica/métodos , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Pronóstico
7.
BMC Cancer ; 19(1): 920, 2019 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-31521128

RESUMEN

BACKGROUND: Tumor-infiltrating immune cells are present in various malignant tumors, but their clinical significance in gastric cancer (GC) remains unclear. This study aimed to investigate the prognostic significance of tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). METHODS: Using a prospective database containing 401 cases of GC, we evaluated TIL (cluster of differentiation 8 (CD8) expression) and TAM (cluster of differentiation 68 (CD68) expression) statuses via immunohistochemical staining. RESULTS: Compared with CD8+ TIL-negative cases (n = 196, 48.6%), CD8+ TIL-positive cases (n = 205, 51.1%) showed significantly better recurrence-free survival (RFS) [log-rank p<0.001; multivariate HR: 0.372; 95% confidence interval (CI): 0.239-0.579, p<0.001]. In contrast, compared with CD68+ TAM-negative cases (n = 217, 54.1%), CD68+ TAM-positive cases (n = 184, 45.9%) had significantly poor RFS [log-rank p<0.001; multivariate HR: 2.182; 95% CI: 1.435-3.318, p<0.001]. Thus, patients with a positive CD8+ TIL and negative CD68+ TAM status exhibited significantly increased RFS. Multivariate analysis demonstrated that CD8+ TILs and CD68+ TAMs may serve as independent prognostic markers for RFS. Incorporating CD8+ TIL and CD68+ TAM statuses into the AJCC TNM system generated a predictive model with better predictive accuracy for RFS. More importantly, patients with a positive TIL and negative TAM status showed a tendency of improved RFS after postoperative adjuvant chemotherapy (PAC). Similar results were obtained by overall survival (OS) analysis. CONCLUSIONS: CD8+ TIL and CD68+ TAM statuses were identified as independent prognostic factors that may be integrated into the current TNM staging system to refine risk stratification and to better predict the survival benefit from PAC in patients with GC. TRIAL REGISTRATION: The current controlled trial was registered at ClinicalTrials.gov (ID: NCT02327481 ) on December 30, 2014.


Asunto(s)
Antígeno B7-2/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores , Linfocitos T CD8-positivos/patología , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Neoplasias Gástricas/etiología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/terapia
8.
J Cancer Res Clin Oncol ; 145(12): 3055-3065, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31522278

RESUMEN

PURPOSE: Combined immunotherapy with anti-programmed cell death-ligand 1 (PD-L1) and an inhibitor of cluster of differentiation 47 (CD47) have exhibited preliminary anti-tumor effect. Our study attempted to describe the PD-L1/CD47 expression status in pulmonary sarcomatoid carcinoma (PSC), and explore its survival impact and relevance with cytotoxic T lymphocytes and macrophages infiltration. METHODS: 148 patients with PSC who underwent surgeries were retrospectively reviewed. Tissue microarrays were conducted for immunohistochemistry (IHC) of PD-L1, CD47, CD8 and CD68. RESULTS: 54 (36.5%) and 78 (52.7%) cases were positive for PD-L1 and CD47, respectively, and 36 (24.3%) of them demonstrated PD-L1/CD47 co-expression. There was a significant correlation between PD-L1 and CD47 expression (P = 0.011). The median overall survival (OS) was 22.5 months (range 0.9-102.4 months). The univariate analysis demonstrated a significantly worse OS in cases with CD47 expression (hazard ratio [HR], 1.66; 95% CI, 1.14-2.42, P = 0.008) and PD-L1/CD47 co-expression (HR, 1.75; 95% CI, 1.15-2.67, P = 0.009). The multivariate analysis demonstrated PD-L1/CD47 co-expression (HR, 1.83; 95% CI, 1.17-2.87, P = 0.008), T stage, M stage, completeness of resection and adjuvant therapy were independent prognostic factors for OS. There was a significant relevance between PD-L1 expression and PD-L1/CD47 co-expression with higher densities of CD8-positive T lymphocytes (P = 0.004, 0.012, respectively) and CD68-positive macrophages (P = 0.026, 0.034, respectively). CONCLUSION: We demonstrated the PD-L1/CD47 co-expression status in PSC. PD-L1 expression correlated with CD47 expression, and PD-L1/CD47 co-expression correlated with poorer prognosis and may serve as a predictive biomarker for combined dual-targeting immunotherapy in PSC patients.


Asunto(s)
Antígeno B7-H1/metabolismo , Antígeno CD47/metabolismo , Carcinoma/metabolismo , Neoplasias Pulmonares/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Carcinoma/patología , Diferenciación Celular/fisiología , Femenino , Humanos , Inmunoterapia/métodos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Pronóstico , Estudios Retrospectivos , Linfocitos T Citotóxicos/metabolismo , Linfocitos T Citotóxicos/patología
9.
Mol Med Rep ; 20(4): 3617-3624, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31485649

RESUMEN

It has been reported that loss and degradation of epidermal melanocytes is closely associated with the pathogenesis of vitiligo. In addition, CD8+ T and regulatory T (Treg) cells serve an important role during these two processes. MicroRNA­155 (miR­155) is known to contribute to the pathogenesis of vitiligo; however, the mechanism by which miR­155 regulates the development of vitiligo remains unclear. In the present study, naïve T and CD8+ T cells were isolated from a patient with non­segmental vitiligo by flow cytometry. The cells were differentiated into Treg cells by treatment with interleukin­2, transforming growth factor­ß and retinoic acid. In addition, miR­155 agonists and antagonists were used to investigate the effect of miR­155 on the proliferation of CD8+ T cells, Treg cells and melanocytes. The results demonstrated that the miR­155 agonist significantly decreased the rate of CD8+ T cell growth, as well as promoted the proliferation of melanocytes by inducing an increase in the percentage of Treg cells. By contrast, the miR­155 antagonist inhibited the proliferation of melanocytes by decreasing the percentage of Treg cells. miR­155 protected melanocyte survival by increasing the number of Treg cells and by decreasing the number of CD8+ T cells. Therefore, these data may provide a new prospect for the treatment of vitiligo.


Asunto(s)
Linfocitos T CD8-positivos/patología , MicroARNs/genética , Linfocitos T Reguladores/patología , Vitíligo/genética , Adulto , Linfocitos T CD8-positivos/citología , Diferenciación Celular , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Humanos , Masculino , Melanocitos/citología , Melanocitos/patología , Persona de Mediana Edad , Linfocitos T Reguladores/citología , Vitíligo/patología
10.
Int J Med Sci ; 16(8): 1142-1148, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31523177

RESUMEN

Background: The aims of this study were to investigate the expression pattern of CDK12 protein in gastric cancer, and to analyze the correlations of CDK12 expression between CD8+ cell density and CCL12 expression. Methods: Eighty-six paired tumor and non-tumor samples were collected from patients who underwent radical surgery and had pathological confirmed gastric adenocarcinoma. Immunohistochemistry was used to assess CDK12 expression and CD8+ cell density. Expression of CDK12 and CCL21 mRNA was detected by quantitative reverse transcription-polymerase chain reaction. Results: CDK12 expression in gastric tumor tissues was significantly higher than it in paired non-tumor tissues (P<0.001). High expression of CDK12 was identified in 43 cases (50%), and it was significantly correlated with Lauren's classification (diffuse type) and number of metastatic lymph nodes (≥15). High CDK12 protein level indicated a relative poorer overall survival than patients with CKD12 low expression, while it was not identified as an independent prognostic factor. Median number of CD8+ cells in tumor tissues was 51 (range: 0-292). Number of CD8+ cells was positively correlated with CDK12 expression score in tumor tissues (r=0.243, P=0.024). Positive correlation was also found between CDK12 and CCL21 mRNA expression (r=0.419, P=0.017). Conclusion: High CDK12 expression was detected in gastric cancer which was correlated with malignant phenotypes and worse outcome. Positive correlations of CD8+ cell number and CCL21 mRNA expression with CDK12 level were identified.


Asunto(s)
Adenocarcinoma/patología , Linfocitos T CD8-positivos/patología , Quimiocina CCL21/metabolismo , Quinasas Ciclina-Dependientes/metabolismo , Neoplasias Gástricas/patología , Adenocarcinoma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos T CD8-positivos/metabolismo , Recuento de Células , Quimiocina CCL21/genética , Quinasas Ciclina-Dependientes/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/metabolismo
11.
Am J Dermatopathol ; 41(9): 644-648, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31433793

RESUMEN

The recently published 2016 revision of the WHO classification of lymphoid neoplasms includes primary cutaneous acral CD8-positive T-cell lymphoma (PCATCL) as a provisional entity. This is a rare indolent lymphoma characterized by papules or nodules on the ear and a dermal infiltrate of CD8-positive T-lymphocytes with cytotoxic marker expression. A retrospective review of a single institutional experience with PCATCL identified 3 patients (mean age 54; range 49-62) with papules or nodules on the ear. Lesional biopsies demonstrated a dense diffuse dermal infiltrate of atypical lymphocytes with a Grenz zone in 2 cases and focal epidermotropism in 1 case. The atypical lymphocytes were predominantly CD3 and CD8 positive with expression of cytotoxic marker TIA1. Staging evaluation failed to reveal systemic disease. Two patients underwent local excision, and the third received local radiation therapy all with complete response and no disease recurrence at last follow-up 3 months (range 2-5 months). Our cases add to the existing limited literature on the clinical and histopathological features of PCATCL. We also performed an updated systematic literature view of the entity.


Asunto(s)
Linfocitos T CD8-positivos/patología , Linfoma Cutáneo de Células T/patología , Linfoma Cutáneo de Células T/terapia , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Biopsia con Aguja , Procedimientos Quirúrgicos Dermatologicos/métodos , Humanos , Inmunohistoquímica , Linfoma Cutáneo de Células T/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Pronóstico , Radioterapia/métodos , Estudios Retrospectivos , Muestreo , Neoplasias Cutáneas/diagnóstico por imagen , Resultado del Tratamiento
12.
ACS Appl Mater Interfaces ; 11(31): 27536-27547, 2019 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-31294958

RESUMEN

Radiotherapy is a traditional method for cancer therapy but may become ineffective likely due to the radiation-induced immunosuppression. Instead of simply increasing the radiation dose, reactivation of immunosuppression in the tumor microenvironment is an alternative strategy for successful cancer treatment. In this work, we synthesized bismuth sulfide nanoparticles (BiNP) and conjugated with immunoactive Ganoderma lucidum polysaccharide (GLP). GLP-BiNP were able to increase the sensitivity of radiotherapy, attributing to the efficient X-ray absorption of bismuth element. BiNP alone can mildly activate dendritic cells (DC) in vitro, while GLP-BiNP further enhanced the level of DC maturation, shown as the increase in phenotypic maturation markers, cytokine release, acid phosphatase activity, and T cell proliferation in DC/T cell co-culture. Compared to BiNP, GLP-BiNP altered the tissue distribution with faster accumulation in the tumor. Meanwhile, mature DC greatly increased in both tumor and spleen by GLP-BiNP within 24 h. GLP-BiNP combination with radiation achieved remarkable inhibition of tumor growth through apoptosis. Alternatively, lung metastasis was largely prohibited by GLP-BiNP, shown as a reduced amount of tumor nodules and cancer cell invasion by pathological findings. Mechanistically, GLP-BiNP altered the tumor immunosuppression microenvironment by preferably increasing the number of intratumor CD8+ T cell proliferation, as well as the improved immunobalance shown as the increased serum interferon-γ/interleukin-4 ratio. Specifically, GLP conjugation seemed to protect the kidney from injury occasionally introduced by bare BiNP. As a result, GLP-BiNP play a dual role in tumor treatment through radiosensitization and immunoactivities.


Asunto(s)
Bismuto , Células Dendríticas/inmunología , Polisacáridos Fúngicos , Nanopartículas , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/radioterapia , Fármacos Sensibilizantes a Radiaciones , Reishi/química , Sulfuros , Animales , Bismuto/química , Bismuto/farmacología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Células Dendríticas/patología , Femenino , Polisacáridos Fúngicos/química , Polisacáridos Fúngicos/farmacología , Inmunidad Celular/efectos de los fármacos , Inmunidad Celular/efectos de la radiación , Interferón gamma/inmunología , Interleucina-4/inmunología , Ratones , Ratones Endogámicos BALB C , Células 3T3 NIH , Nanopartículas/química , Nanopartículas/uso terapéutico , Neoplasias Experimentales/patología , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/farmacología , Sulfuros/química , Sulfuros/farmacología
13.
PLoS One ; 14(7): e0215883, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31291255

RESUMEN

Innate CD8αα+ cells, also referred to as iCD8α cells, are TCR-negative intraepithelial lymphocytes (IEL) possessing cytokine and chemokine profiles and functions related to innate immune cells. iCD8α cells constitute an important source of osteopontin in the intestinal epithelium. Osteopontin is a pleiotropic cytokine with diverse roles in bone and tissue remodeling, but also has relevant functions in the homeostasis of immune cells. In this report, we present evidence for the role of iCD8α cells in the homeostasis of TCR-negative NKp46+NK1.1+ IEL (ILC1-like). We also show that the effect of iCD8α cells on ILC1-like IEL is enhanced in vitro by osteopontin. We show that in the absence of iCD8α cells, the number of NKp46+NK1.1+ IEL is significantly reduced. These ILC1-like cells are involved in intestinal pathogenesis in the anti-CD40 mouse model of intestinal inflammation. Reduced iCD8α cell numbers results in a milder form of intestinal inflammation in this disease model, whereas treatment with osteopontin increases disease severity. Collectively, our results suggest that iCD8α cells promote survival of NKp46+NK1.1+ IEL, which significantly impacts the development of intestinal inflammation.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Mucosa Intestinal/inmunología , Linfocitos Intraepiteliales/inmunología , Animales , Antígenos CD8/metabolismo , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Supervivencia Celular/inmunología , Gastroenteritis/etiología , Gastroenteritis/inmunología , Gastroenteritis/patología , Homeostasis/inmunología , Inmunidad Innata , Mucosa Intestinal/patología , Linfocitos Intraepiteliales/metabolismo , Linfocitos Intraepiteliales/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Osteopontina/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo
14.
Nat Immunol ; 20(9): 1231-1243, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31358999

RESUMEN

Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant models, simultaneous anti-PD-1 and vaccine therapy reversed resistance, while PD-1 blockade before antigen priming abolished therapeutic outcomes. This was due to induction of dysfunctional PD-1+CD38hi CD8+ cells by PD-1 blockade in suboptimally primed CD8 cell conditions induced by tumors. This results in erroneous T cell receptor signaling and unresponsiveness to antigenic restimulation. On the other hand, PD-1 blockade of optimally primed CD8 cells prevented the induction of dysfunctional CD8 cells, reversing resistance. Depleting PD-1+CD38hi CD8+ cells enhanced therapeutic outcomes. Furthermore, non-responding patients showed more PD-1+CD38+CD8+ cells in tumor and blood than responders. In conclusion, the status of CD8+ T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1+CD38hi CD8+ cells that is reversed by optimal priming. PD-1+CD38hi CD8+ cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy.


Asunto(s)
ADP-Ribosil Ciclasa 1/metabolismo , Linfocitos T CD8-positivos/inmunología , Resistencia a Antineoplásicos/inmunología , Glicoproteínas de Membrana/metabolismo , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/inmunología , ADP-Ribosil Ciclasa 1/genética , Animales , Anticuerpos/inmunología , Linfocitos T CD8-positivos/patología , Vacunas contra el Cáncer/inmunología , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Inmunoterapia/métodos , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Microambiente Tumoral/inmunología
15.
Nature ; 571(7766): 565-569, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31316206

RESUMEN

Parkinson's disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles1,2. An early-onset form of Parkinson's disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes3. PINK1 and Parkin (encoded by PRKN) are involved in the clearance of damaged mitochondria in cultured cells4, but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo5-8. It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens9, which suggests that autoimmune mechanisms participate in the aetiology of Parkinson's disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1-/- mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with L-DOPA. These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson's disease, which highlights the relevance of the gut-brain axis in the disease10.


Asunto(s)
Infecciones por Enterobacteriaceae/microbiología , Infecciones por Enterobacteriaceae/fisiopatología , Intestinos/microbiología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/microbiología , Proteínas Quinasas/deficiencia , Proteínas Quinasas/genética , Animales , Presentación de Antígeno/inmunología , Autoantígenos/inmunología , Axones/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Citrobacter rodentium/inmunología , Citrobacter rodentium/patogenicidad , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/inmunología , Neuronas Dopaminérgicas/patología , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Enterobacteriaceae/patología , Femenino , Intestinos/inmunología , Intestinos/patología , Levodopa/uso terapéutico , Masculino , Ratones , Mitocondrias/inmunología , Mitocondrias/patología , Neostriado/inmunología , Neostriado/microbiología , Neostriado/patología , Neostriado/fisiopatología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Proteínas Quinasas/inmunología , Ubiquitina-Proteína Ligasas/deficiencia , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/inmunología
16.
PLoS Pathog ; 15(6): e1007890, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31220189

RESUMEN

Cytomegalovirus (CMV) is a ubiquitous herpesvirus infecting most of the world's population. CMV has been rigorously investigated for its impact on lifelong immunity and potential complications arising from lifelong infection. A rigorous adaptive immune response mounts during progression of CMV infection from acute to latent states. CD8 T cells, in large part, drive this response and have very clearly been demonstrated to take up residence in the salivary gland and lungs of infected mice during latency. However, the role of tissue resident CD8 T cells as an ongoing defense mechanism against CMV has not been studied in other anatomical locations. Therefore, we sought to identify additional locations of anti-CMV T cell residency and the physiological consequences of such a response. Through RT-qPCR we found that mouse CMV (mCMV) infected the visceral adipose tissue and that this resulted in an expansion of leukocytes in situ. We further found, through flow cytometry, that adipose tissue became enriched in cytotoxic CD8 T cells that are specific for mCMV antigens from day 7 post infection through the lifespan of an infected animal (> 450 days post infection) and that carry markers of tissue residence. Furthermore, we found that inflammatory cytokines are elevated alongside the expansion of CD8 T cells. Finally, we show a correlation between the inflammatory state of adipose tissue in response to mCMV infection and the development of hyperglycemia in mice. Overall, this study identifies adipose tissue as a location of viral infection leading to a sustained and lifelong adaptive immune response mediated by CD8 T cells that correlates with hyperglycemia. These data potentially provide a mechanistic link between metabolic syndrome and chronic infection.


Asunto(s)
Tejido Adiposo , Linfocitos T CD8-positivos , Infecciones por Herpesviridae , Hiperglucemia , Muromegalovirus/inmunología , Paniculitis , Tejido Adiposo/inmunología , Tejido Adiposo/patología , Tejido Adiposo/virología , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Infecciones por Herpesviridae/genética , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/patología , Infecciones por Herpesviridae/virología , Hiperglucemia/genética , Hiperglucemia/inmunología , Hiperglucemia/patología , Hiperglucemia/virología , Memoria Inmunológica , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Inflamación/virología , Ratones , Ratones Noqueados , Paniculitis/genética , Paniculitis/inmunología , Paniculitis/patología , Paniculitis/virología
17.
PLoS Pathog ; 15(6): e1007797, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31220194

RESUMEN

During viral infection, tight regulation of CD8+ T-cell functions determines the outcome of the disease. Recently, others and we determined that the natural killer (NK) cells kill hyperproliferative CD8+ T cells in the context of viral infection, but molecules that are involved in shaping the regulatory capability of NK cells remain virtually unknown. Here we used mice lacking the Fc-receptor common gamma chain (FcRγ, FcεRIγ, Fcer1g-/- mice) to determine the role of Fc-receptor and NK-receptor signaling in the process of CD8+ T-cell regulation. We found that the lack of FcRγ on NK cells limits their ability to restrain virus-specific CD8+ T cells and that the lack of FcRγ in Fcer1g-/- mice leads to enhanced CD8+ T-cell responses and rapid control of the chronic docile strain of the lymphocytic choriomeningitis virus (LCMV). Mechanistically, FcRγ stabilized the expression of NKp46 but not that of other killer cell-activating receptors on NK cells. Although FcRγ did not influence the development or activation of NK cell during LCMV infection, it specifically limited their ability to modulate CD8+ T-cell functions. In conclusion, we determined that FcRγ plays an important role in regulating CD8+ T-cell functions during chronic LCMV infection.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Activación de Linfocitos , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Receptores Fc/inmunología , Enfermedad Aguda , Animales , Antígenos Ly/genética , Antígenos Ly/inmunología , Linfocitos T CD8-positivos/patología , Enfermedad Crónica , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Coriomeningitis Linfocítica/genética , Coriomeningitis Linfocítica/patología , Ratones , Ratones Noqueados , Receptor 1 Gatillante de la Citotoxidad Natural/genética , Receptor 1 Gatillante de la Citotoxidad Natural/inmunología , Receptores Fc/genética
18.
Nature ; 571(7764): 211-218, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31207603

RESUMEN

Exhausted CD8+ T (Tex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (Teff) or memory (Tmem) CD8+ T cells. Tex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, Tex cells are a distinct immune subset, with a unique chromatin landscape compared with Teff and Tmem cells. However, the mechanisms that govern the transcriptional and epigenetic development of Tex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of Tex cells in mice. TOX is largely dispensable for the formation of Teff and Tmem cells, but it is critical for exhaustion: in the absence of TOX, Tex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in Tex cells. Robust expression of TOX therefore results in commitment to Tex cells by translating persistent stimulation into a distinct Tex cell transcriptional and epigenetic developmental program.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Epistasis Genética , Proteínas de Homeodominio/metabolismo , Transcripción Genética , Animales , Calcineurina/metabolismo , Señalización del Calcio , Retroalimentación Fisiológica , Femenino , Regulación de la Expresión Génica/inmunología , Genotipo , Memoria Inmunológica , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/metabolismo , Escape del Tumor
19.
Nature ; 571(7764): 270-274, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31207604

RESUMEN

Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states1-6. Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, 'non-exhausted' immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Diferenciación Celular/inmunología , Proteínas del Grupo de Alta Movilidad/metabolismo , Proteínas de Homeodominio/metabolismo , Neoplasias/inmunología , Animales , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Proteínas del Grupo de Alta Movilidad/deficiencia , Proteínas del Grupo de Alta Movilidad/genética , Proteínas de Homeodominio/genética , Humanos , Memoria Inmunológica , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Ratones , Neoplasias/patología , Fenotipo , Receptores de Antígenos de Linfocitos T/inmunología , Transcripción Genética
20.
Nature ; 571(7764): 265-269, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31207605

RESUMEN

Cytotoxic T cells are essential mediators of protective immunity to viral infection and malignant tumours and are a key target of immunotherapy approaches. However, prolonged exposure to cognate antigens often attenuates the effector capacity of T cells and limits their therapeutic potential1-4. This process, known as T cell exhaustion or dysfunction1, is manifested by epigenetically enforced changes in gene regulation that reduce the expression of cytokines and effector molecules and upregulate the expression of inhibitory receptors such as programmed cell-death 1 (PD-1)5-8. The underlying molecular mechanisms that induce and stabilize the phenotypic and functional features of exhausted T cells remain poorly understood9-12. Here we report that the development and maintenance of populations of exhausted T cells in mice requires the thymocyte selection-associated high mobility group box (TOX) protein13-15. TOX is induced by high antigen stimulation of the T cell receptor and correlates with the presence of an exhausted phenotype during chronic infections with lymphocytic choriomeningitis virus in mice and hepatitis C virus in humans. Removal of its DNA-binding domain reduces the expression of PD-1 at the mRNA and protein level, augments the production of cytokines and results in a more polyfunctional T cell phenotype. T cells with this deletion initially mediate increased effector function and cause more severe immunopathology, but ultimately undergo a massive decline in their quantity, notably among the subset of TCF-1+ self-renewing T cells. Altogether, we show that TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infection, and provide a link between the suppression of effector function intrinsic to CD8 T cells and protection against immunopathology.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/virología , Proteínas del Grupo de Alta Movilidad/metabolismo , Proteínas de Homeodominio/metabolismo , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/virología , Animales , Proliferación Celular , Enfermedad Crónica , Citocinas/inmunología , Citocinas/metabolismo , Epigénesis Genética , Femenino , Regulación de la Expresión Génica/inmunología , Hepacivirus/inmunología , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Humanos , Memoria Inmunológica , Virus de la Coriomeningitis Linfocítica/inmunología , Masculino , Ratones , Fenotipo , Timocitos/citología , Timocitos/inmunología , Transcripción Genética
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