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1.
Nat Commun ; 15(1): 9106, 2024 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-39438472

RESUMEN

Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm preferentially involving the upper aerodigestive tract. Here we show that NK-cell-specific Trp53 disruption in mice leads to the development of NK-cell lymphomas after long latency, which involve not only the hematopoietic system but also the salivary glands. Before tumor onset, Trp53 knockout causes extensive gene expression changes, resulting in immature NK-cell expansion, exclusively in the salivary glands. Both human and murine NK-cell lymphomas express tissue-resident markers, suggesting tissue-resident NK cells as their cell-of-origin. Murine NK-cell lymphomas show recurrent Myc amplifications and upregulation of MYC target gene signatures. EBV-encoded latent membrane protein 1 expression accelerates NK-cell lymphomagenesis and causes diverse microenvironmental changes, particularly myeloid propagation, through interferon-γ signaling. In turn, myeloid cells support tumor cells via CXCL16-CXCR6 signaling and its inhibition is effective against NK-cell tumors in vivo. Remarkably, KLRG1-expressing cells expand in the tumor and are capable of repopulating tumors in secondary recipients. Furthermore, targeting KLRG1 alone or combined with MYC inhibition using an eIF4 inhibitor is effective against NK-cell tumors. Therefore, our observations provide insights into the pathogenesis and highlight potential therapeutic targets, including CXCL16, KLRG1, and MYC, in ENKTCL, which can help improve its diagnostic and therapeutic strategies.


Asunto(s)
Células Asesinas Naturales , Linfoma Extranodal de Células NK-T , Proteínas Proto-Oncogénicas c-myc , Microambiente Tumoral , Proteína p53 Supresora de Tumor , Animales , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Ratones , Microambiente Tumoral/inmunología , Linfoma Extranodal de Células NK-T/genética , Linfoma Extranodal de Células NK-T/metabolismo , Linfoma Extranodal de Células NK-T/virología , Linfoma Extranodal de Células NK-T/patología , Humanos , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Ratones Noqueados , Modelos Animales de Enfermedad , Interferón gamma/metabolismo , Receptores CXCR6/metabolismo , Receptores CXCR6/genética , Quimiocina CXCL16/metabolismo , Quimiocina CXCL16/genética , Herpesvirus Humano 4 , Regulación Neoplásica de la Expresión Génica , Transducción de Señal , Glándulas Salivales/patología , Glándulas Salivales/metabolismo , Células Mieloides/metabolismo , Línea Celular Tumoral , Ratones Endogámicos C57BL
2.
Pathology ; 2024 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-39266421

RESUMEN

Adult T-cell leukaemia/lymphoma (ATLL) is an aggressive peripheral T-cell neoplasm with a poor prognosis. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an immune checkpoint receptor expressed on T and natural killer cells. Although increased TIGIT expression in the tumour microenvironment is associated with poor prognosis in various neoplasms, its relevance in ATLL remains unknown. Herein, we investigated the clinicopathological impact of TIGIT expression on ATLL using immunohistochemistry. TIGIT expression was detected in 21 of 84 patients (25%). A partial association between the clinical features and immune checkpoint molecules and the expression of TIGIT was found including sIL-2R, CD86 and GITR. TIGIT-positive patients [median survival time (MST) 8.9 months, 95% confidence interval (CI) 7.7-15.6] had inferior overall survival compared with TIGIT-negative patients (MST 18.7 months, 95% CI 12.0-36.4) (p=0.0124]. TIGIT expression maintained its prognostic value for overall survival in both univariate and multivariate analyses [hazard ratio (HR) 1.909; 95% CI 1.044-3.488; p=0.0356]. Further studies are required to clarify the clinical and biological significance of TIGIT expression in patients with ATLL.

4.
Breast Cancer ; 31(3): 340-346, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38570435

RESUMEN

The Japanese Breast Cancer Society Clinical Practice Guidelines for Breast Cancer, 2022 Edition was published in June 2022. The guidelines were prepared while conforming as much as possible to the "Minds Manual for Guideline Development 2020 ver. 3.0." edited by the Minds Manual Development Committee of the Japan Council for Quality Health Care in 2021. In addition, a survey of Japanese Breast Cancer Society members on the 2018 edition of the guidelines was conducted from February 19 to March 4, 2021. Based on the responses from over 600 members, original innovations were made to make the guidelines more user-friendly. The 2018 edition of the guidelines was developed to provide support tools for physicians and patients to utilize shared decision-making. The 2022 guidelines consist of two volumes: (1) an "Epidemiology and Diagnosis" section covering "Screening and Diagnosis", "Radiological diagnosis", and "Pathological diagnosis", and (2) a "Treatment" section covering "Surgical therapy", "Radiation therapy", and "Systemic therapy". We believe that this concise summary of the guidelines will be useful to physicians and researchers in Japan and overseas.


Asunto(s)
Neoplasias de la Mama , Humanos , Neoplasias de la Mama/terapia , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Femenino , Japón , Sociedades Médicas , Guías de Práctica Clínica como Asunto , Oncología Médica/normas , Pueblos del Este de Asia
5.
Cancer Med ; 13(6): e7050, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38506241

RESUMEN

AIMS: T-follicular helper (TFH) cells are effector T-cells that are crucial for B-cell selection and differentiation. T-cell lymphomas derived from TFH cells have distinct characteristics. Additionally, in the World Health Organization (WHO) classification 5th edition, three lymphomas were introduced as independent disease entities with TFH cell origin. We aimed to investigate the clinicopathological features of adult T-cell leukemia/lymphoma (ATLL) with a TFH phenotype (TFHP). METHODS AND RESULTS: We performed TFH immunohistochemistry analysis of five biomarkers for the biopsy specimen, with TFHP being indicated by a positive result for more than two markers. Among 75 cases of ATLL, 37.3% of them showed TFHP. Compared with cases of ATLL without TFHP, cases of ATLL with TFHP showed higher C-reactive protein levels (p = 0.0219) and increased high endothelial venule proliferation (p = 0.024). However, there were no significant between-group differences in overall survival as well as other clinical and morphological findings. Furthermore, there was no significant between-group difference in TFH markers and FOXP3 expression. CONCLUSION: Some patients with ATLL may present a TFHP, which should not preclude the diagnosis of ATLL. Although presenting a TFHP does not affect prognosis, it is important to identify cases of ATLL with a TFHP since it may inform future treatment strategies.


Asunto(s)
Leucemia-Linfoma de Células T del Adulto , Linfoma , Adulto , Humanos , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Leucemia-Linfoma de Células T del Adulto/genética , Linfoma/patología , Pronóstico , Fenotipo , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/patología
6.
Cancer Res Commun ; 4(3): 723-737, 2024 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-38380966

RESUMEN

Small cell lung cancer (SCLC) is exceptionally aggressive, with limited treatment options. Disialoganglioside (GD2) is highly expressed on SCLC and is considered a good target for chimeric antigen receptor (CAR) T cells (CART). Although GD2-directed CARTs (GD2-CART) exhibit cytotoxicity against various GD2-expressing tumors, they lack significant cytotoxicity against SCLC. To enhance cytotoxicity of GD2-CARTs against SCLC, we introduced GD2-CAR into induced pluripotent stem cells (iPSC)-derived rejuvenated cytotoxic T lymphocytes (GD2-CARrejT). GD2-CARrejTs acted much more strongly against SCLC cells than did GD2-CARTs both in vitro and in vivo. Single-cell RNA sequencing elucidated that levels of expression of TIGIT were significantly lower and levels of expression of genes associated with cytotoxicity were significantly higher in GD2-CARrejTs than those in GD2-CARTs. Dual blockade of TIGIT and programmed death-1 (PD-1) increased the cytotoxicity of GD2-CARTs to some extent, suggesting that low TIGIT and PD-1 expression by GD2-CARrejTs is a major factor required for robust cytotoxicity against SCLC. Not only for robust cytotoxicity but also for availability as "off-the-shelf" T-cell therapy, iPSC-derived GD2-CARrejTs are a promising novel treatment for SCLC. SIGNIFICANCE: This research introduces iPSC-derived rejuvenated GD2-CARTs (GD2-CARrejT) as a novel approach to combat SCLC. Compared with conventional GD2-CARTs, GD2-CARrejTs with reduced TIGIT and PD-1 expression demonstrate robust cytotoxicity against SCLC and would be a promising therapy for SCLC.


Asunto(s)
Células Madre Pluripotentes Inducidas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Inmunoterapia Adoptiva , Receptor de Muerte Celular Programada 1
7.
Cancer Med ; 13(3): e6793, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38234210

RESUMEN

AIM: Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a heterogeneous disease that can be classified into the PTCL-TBX21 and PTCL-GATA3 subtypes. METHODS: In this study, we compared the clinicopathological features of PTCL-NOS in a Japanese cohort, classified using an IHC algorithm. RESULTS: One hundred patients with PTCL-NOS were categorized as having PTCL-TBX21 (n = 55), PTCL-GATA3 (n = 24), or PTCL-unclassified (n = 21). When comparing PTCL-TBX21 and PTCL-GATA3, PTCL-TBX21 showed significantly lower CD4 positivity (p = 0.047), lower counts of high endothelial venules (p = 0.032), and a tendency for a better response to initial treatment (p = 0.088). Gene expression analysis using the nCounter system showed higher expression of tumor immunity-related genes, such as PD-L1, LAG3, and IDO1, in PTCL-TBX21 than in PTCL-GATA3. PTCL-GATA3 had significantly worse overall survival (OS) than those with PTCL-TBX21 (p = 0.047), although a similar tendency was observed for progression-free survival (PFS) (p = 0.064). PTCL-GATA3 was a prognostic factor for OS in univariate analysis (HR 2.02; 95% CI, 1.09-3.77; p = 0.027), although multivariate analysis did not show significance (HR 2.07; 95% CI, 0.93-4.61; p = 0.074). In the PFS analysis, PTCL-GATA3 was an independent prognostic factor by univariate analysis (HR 1.96; 95% CI, 1.08-3.56; p = 0.027) and multivariate analysis (HR 2.34; 95% CI, 1.07-5.11; p = 0.032). CONCLUSION: The classification of PTCL-NOS into PTCL-TBX21 and PTCL-GATA3 is useful for predicting the prognosis of Japanese patients and stratifying the administration of tumor immune checkpoint inhibitors in clinical practice.


Asunto(s)
Algoritmos , Linfoma de Células T Periférico , Humanos , Japón , Perfilación de la Expresión Génica , Inhibidores de Puntos de Control Inmunológico , Linfoma de Células T Periférico/tratamiento farmacológico , Linfoma de Células T Periférico/genética , Factor de Transcripción GATA3/genética
8.
Pathol Res Pract ; 254: 155117, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38262270

RESUMEN

Regulatory B cells (Bregs) suppress antitumor immunity by producing anti-inflammatory cytokines such as transforming growth factor ß (TGF-ß) and interleukin-10 (IL-10) and promoting tumor growth. It is unknown whether diffuse large B-cell lymphoma (DLBCL), a common subtype of B-cell malignancy, exhibits characteristics similar to those of Bregs. This study aimed to clarify the features of DLBCLs carrying Breg markers. In 123 DLBCL cases, we evaluated TGF-ß and IL-10 expression in tumor biopsy samples using immunohistochemical staining and retrospectively analyzed their clinicopathological characteristics. Fifteen cases (12.2 %) classified as Breg-type DLBCL were positive for both TGF-ß and IL-10. Breg-type DLBCL is mainly classified as having activated B cell-like cells of origin. Breg-type DLBCL cases showed significantly worse progression-free survival and overall survival (OS) than other DLBCL cases (P = 0.0016 and P = 0.042, respectively). In multivariate analysis, Breg-type DLBCL significantly affected OS (hazard ratio, 3.13; 95 % confidence interval 1.15-8.55; P = 0.025). Gene expression analysis showed that the expression of follicular dendritic cell-associated genes (FCER2, PIK3CD, FOXO1) was downregulated in Breg-type DLBCLs compared to other DLBCLs. These results suggest that the double expression of Breg markers, TGF-ß and IL-10, in tumor cells indicates a poor prognosis in DLBCL patients. Further studies evaluating genomic abnormalities could confirm the characteristics of Breg-type DLBCL.


Asunto(s)
Linfocitos B Reguladores , Linfoma de Células B Grandes Difuso , Humanos , Interleucina-10 , Pronóstico , Factor de Crecimiento Transformador beta , Linfocitos B Reguladores/química , Linfocitos B Reguladores/metabolismo , Linfocitos B Reguladores/patología , Estudios Retrospectivos , Biomarcadores de Tumor/análisis , Linfoma de Células B Grandes Difuso/patología
10.
Breast Cancer ; 31(2): 157-164, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37973686

RESUMEN

This article provides updates to readers based on the newly published Japanese Breast Cancer Society Clinical Practice Guidelines for Breast Cancer Screening and Diagnosis, 2022 Edition. These guidelines incorporate the latest evaluation of evidence from studies of diagnostic accuracy. For each clinical question, outcomes for benefits and harms were established, and qualitative or quantitative systematic reviews were conducted. Recommendations were determined through voting by a multidisciplinary group, and guidelines were documented to facilitate shared decision-making among patients and medical professionals. The guidelines address screening, surveillance, and pre- and postoperative diagnosis of breast cancer. In an environment that demands an integrated approach, decisions are needed on how to utilize modalities, such as mammography, ultrasound, MRI, and PET/CT. Additionally, it is vital to understand the appropriate use of new technologies, such as tomosynthesis, elastography, and contrast-enhanced ultrasound, and to consider how best to adapt these methods for individual patients.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/diagnóstico por imagen , Japón , Tomografía Computarizada por Tomografía de Emisión de Positrones , Detección Precoz del Cáncer/métodos , Mamografía/métodos , Tamizaje Masivo
11.
Pathology ; 56(1): 81-91, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38110323

RESUMEN

Myeloid sarcoma is a rare extramedullary haematopoietic malignancy. Interaction between CD47 and signal regulatory protein α (SIRPα) inhibits phagocytosis. CD47-positive tumours confer poor prognoses in various malignant tumours, including acute myeloid leukaemia. This study aimed to investigate the clinicopathological effects of CD47 and SIRPα expression in myeloid sarcoma. Immunohistochemistry (IHC) of CD47 and SIRPα was performed in 84 biopsy samples obtained from patients with myeloid sarcoma, some of which were CD47-positive. Patients were categorised into the following two groups based on IHC of SIRPα: those with SIRPα-positive neoplastic cells (nSIRPα) and, SIRPα expression on non-neoplastic stromal cells in tumour microenvironment (miSIRPα). In addition, patients with CD47 positivity had higher lymphocytic infiltration into the tumour microenvironment. Overall, these patients had significantly higher overall survival, however, no significant difference was observed in progression-free survival. No significant prognostic differences were observed between the nSIRPα and miSIRPα groups. This is the first study to demonstrate an association between CD47 expression and improved prognosis in myeloid sarcoma. Nonetheless, it will be necessary to conduct additional research on gene expression and genomic abnormalities to elucidate the corresponding pathogenesis of myeloid sarcoma.


Asunto(s)
Leucemia Mieloide Aguda , Sarcoma Mieloide , Humanos , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Pronóstico , Sarcoma Mieloide/diagnóstico , Antígenos de Diferenciación/genética , Antígenos de Diferenciación/metabolismo , Antígeno CD47/genética , Microambiente Tumoral
13.
Virchows Arch ; 483(2): 255-260, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37270432

RESUMEN

Classic Hodgkin lymphoma (CHL) harbors a small number of Hodgkin-Reed-Sternberg (HRS) cells scattered among numerous lymphocytes. HRS cells are surrounded by distinct CD4+ T cells in a rosette-like manner. These CD4+ T cell rosettes play an important role in the tumor microenvironment (TME) of CHL. To elucidate the interaction between HRS cells and CD4+ T cell rosettes, we completed digital spatial profiling to compare the gene expression profiles of CD4+ T cell rosettes and other CD4+ T cells separated from the HRS cells. Immune checkpoint molecules including OX40, programed cell death-1 (PD-1), and cytotoxic T lymphocyte associated protein 4 (CTLA-4) expression was higher in CD4+ T cell rosettes compared to other CD4+ T cells. Immunohistochemistry confirmed variable PD-1, CTLA-4, and OX40 expression in the CD4+ T cell rosettes. This study introduced a new pathological approach to study the CHL TME, and provided deeper insight into CD4+ T cells in CHL.


Asunto(s)
Enfermedad de Hodgkin , Humanos , Enfermedad de Hodgkin/patología , Linfocitos T/metabolismo , Antígeno CTLA-4 , Receptor de Muerte Celular Programada 1/metabolismo , Células de Reed-Sternberg/metabolismo , Linfocitos T CD4-Positivos , Microambiente Tumoral
14.
Blood Cancer Discov ; 4(5): 374-393, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37162520

RESUMEN

Acceleration of glycolysis is a common trait of cancer. A key metabolite, lactate, is typically secreted from cancer cells because its accumulation is toxic. Here, we report that a viral oncogene, HTLV-1 bZIP factor (HBZ), bimodally upregulates TAp73 to promote lactate excretion from adult T-cell leukemia-lymphoma (ATL) cells. HBZ protein binds to EZH2 and reduces its occupancy of the TAp73 promoter. Meanwhile, HBZ RNA activates TAp73 transcription via the BATF3-IRF4 machinery. TAp73 upregulates the lactate transporters MCT1 and MCT4. Inactivation of TAp73 leads to intracellular accumulation of lactate, inducing cell death in ATL cells. Furthermore, TAp73 knockout diminishes the development of inflammation in HBZ-transgenic mice. An MCT1/4 inhibitor, syrosingopine, decreases the growth of ATL cells in vitro and in vivo. MCT1/4 expression is positively correlated with TAp73 in many cancers, and MCT1/4 upregulation is associated with dismal prognosis. Activation of the TAp73-MCT1/4 pathway could be a common mechanism contributing to cancer metabolism. SIGNIFICANCE: An antisense gene encoded in HTLV-1, HBZ, reprograms lactate metabolism and epigenetic modification by inducing TAp73 in virus-positive leukemic cells. A positive correlation between TAp73 and its target genes is also observed in many other cancer cells, suggesting that this is a common mechanism for cellular oncogenesis. This article is featured in Selected Articles from This Issue, p. 337.


Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Ratones , Animales , Virus Linfotrópico T Tipo 1 Humano/genética , Virus Linfotrópico T Tipo 1 Humano/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/metabolismo , Ratones Transgénicos , Epigénesis Genética , Lactatos
15.
Breast Cancer ; 29(4): 636-644, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35303282

RESUMEN

BACKGROUND: We carried out the first multi-institutional prospective study on accelerated partial breast irradiation (APBI) via multicatheter interstitial brachytherapy in a shorter period for early breast cancer in Japan. METHODS: Patient eligibility criteria included positive hormone receptors, tumors ≤ 3 cm and TNM stage pN0M0. After breast-conserving surgery (Japanese cylindrical resection) and histological confirmation of negative surgical margins and the absence of lymph node metastasis, applicator implantation was performed either postoperatively or intraoperatively. High-dose-rate brachytherapy of 36 Gy in 6 fractions was delivered. RESULTS: Forty-six patients from six institutions received this treatment regimen, and the median follow-up time was 60 months (range 57-67 months). The median resected breast tissue volume was 81 cm3 (range 28-260 cm3). No Grade 4 late sequela, local recurrence nor death due to breast cancer were observed. Grade 2-3 sequelae such as rib fracture (2%), soft tissue necrosis (9%), fibrosis (20%), and breast pain (9%) were observed. The resected breast tissue volumes of the patients who had Grade ≥ 2 fibrosis and Grade < 2 fibrosis were 105.9 ± 32.3 cm3 and 76.3 ± 45.6 cm3, respectively, p = 0.02. The overall cosmetic outcome score of Excellent/Good was 74% at 60 months after APBI. Grade ≥ 1 fibrosis was observed in 44% and 92% of patients who scored Excellent/Good and Fair/Poor, respectively, p = 0.004. CONCLUSIONS: This study showed excellent local control and survival results with minimal late sequelae.


Asunto(s)
Braquiterapia , Neoplasias de la Mama , Braquiterapia/métodos , Neoplasias de la Mama/patología , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Terapia Combinada , Estudios de Factibilidad , Femenino , Fibrosis , Estudios de Seguimiento , Humanos , Japón , Mastectomía Segmentaria/métodos , Estudios Prospectivos , Dosificación Radioterapéutica , Resultado del Tratamiento
16.
Hematol Oncol ; 40(4): 530-540, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35122292

RESUMEN

Follicular lymphoma (FL) is characterized by an indolent clinical course and a high relapse rate, and often exhibits a diffuse pattern beyond the follicular area. Our group previously reported that immune checkpoint (ICP) pathways, such as programmed cell death (PD-1) and programmed death ligand 1 (PD-L1), are poor prognostic factors for diffuse large B-cell lymphoma and adult T-cell leukemia/lymphoma. In this study, the association between the expression of multiple ICP molecules according to immunohistochemistry and clinicopathological features in FL was determined via immunostaining of 173 biopsy samples. Membrane and/or cytoplasm expression of CD86 (nCD86) and PD-L1 (nPD-L1) was found in tumor cells, whereas PD-1 (miPD-1), Galectin-9 (miGalectin-9), OX40 (miOX40), CTLA-4 (miCTLA-4), Tim-3 (miTim-3), OX40L (miOX40L), and LAG-3 (miLAG-3) were expressed in non-neoplastic stromal cells. MiPD-1 expression was significantly higher in the follicular area than in the diffuse area (p = 0.0450). Expression of miOX40 and miCTLA-4 was significantly higher in the diffuse area than in the follicular area (respectively, p = 0.0053 and p = 0.0092). MiTim-3 tended to be higher in the diffuse area than in the follicular area (p = 0.0616). MiTim-3 was significantly higher in relapse cases than in new-onset cases (p = 0.0440); miLAG-3 tended to be higher in relapse cases than in new-onset cases (p = 0.0622, not significant). The miOX40L-high FL group had a significantly worse overall survival than the miOX40L-low group (p = 0.0320). The expression of multiple ICP molecules on several cells reflects activated anti-tumor immunity and the unique FL microenvironment. Further studies on gene expression or genomic abnormalities will reveal the clinical and biological significance of ICP molecules in FL.


Asunto(s)
Linfoma Folicular , Linfoma de Células B Grandes Difuso , Adulto , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Antígeno CTLA-4 , Galectinas , Receptor 2 Celular del Virus de la Hepatitis A , Humanos , Proteínas de Punto de Control Inmunitario , Linfoma de Células B Grandes Difuso/patología , Pronóstico , Receptor de Muerte Celular Programada 1/metabolismo , Recurrencia , Microambiente Tumoral
17.
Ann Hematol ; 101(5): 1067-1075, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35171311

RESUMEN

CD37 is a tetraspanin protein expressed in various B-cell lymphomas that mediates tumor survival signaling. Follicular lymphoma (FL) is a representative B-cell neoplasm composed of germinal center B cells. In recent years, CD37 has been focused on as a therapeutic target for B-cell lymphoma. The purpose of this study was to characterize CD37 expression in FL patients to identify risk factors associated with various prognostic factors. We retrospectively reviewed 167 cases of FL and evaluated the immunohistochemical expression of CD37 and its statistical association with clinicopathological features. Immunohistochemically, CD37 was observed in the cytoplasm and/or membrane of neoplastic cells, mainly in neoplastic follicles to various extents. One hundred cases (100/167, 60.0%) were categorized as CD37-positive, and 67 cases were CD37-negative. In cases with high Follicular Lymphoma International Prognostic Index (FLIPI), CD37-negative cases had a poor overall survival compared with CD37-positive cases (P = 0.047), although no significant differences were observed in other clinicopathologic factors, including histological grade, BCL2-IGH translocation, and immunohistochemical phenotype. Therefore, CD37 protein may play a role in tumor progression and may serve as a therapeutic target. However, further studies are needed to explore its significance.


Asunto(s)
Linfoma de Células B , Linfoma Folicular , Antígenos de Neoplasias/genética , Linfocitos B/patología , Centro Germinal/patología , Humanos , Linfoma de Células B/patología , Estudios Retrospectivos , Tetraspaninas/genética , Tetraspaninas/metabolismo
18.
Mol Ther ; 30(2): 534-549, 2022 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-34628050

RESUMEN

We generated dual-antigen receptor (DR) T cells from induced pluripotent stem cells (iPSCs) to mitigate tumor antigen escape. These cells were engineered to express a chimeric antigen receptor (CAR) for the antigen cell surface latent membrane protein 1 (LMP1; LMP1-CAR) and a T cell receptor directed to cell surface latent membrane protein 2 (LMP2), in association with human leucocyte antigen A24, to treat therapy-refractory Epstein-Barr virus-associated lymphomas. We introduced LMP1-CAR into iPSCs derived from LMP2-specific cytotoxic T lymphocytes (CTLs) to generate rejuvenated CTLs (rejTs) active against LMP1 and LMP2, or DRrejTs. All DRrejT-treated mice survived >100 days. Furthermore, DRrejTs rejected follow-up inocula of lymphoma cells, demonstrating that DRrejTs persisted long-term. We also demonstrated that DRrejTs targeting CD19 and LMP2 antigens exhibited a robust tumor suppressive effect and conferred a clear survival advantage. Co-operative antitumor effect and in vivo persistence, with unlimited availability of DRrejT therapy, will provide powerful and sustainable T cell immunotherapy.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Células Madre Pluripotentes Inducidas , Linfoma , Receptores Quiméricos de Antígenos , Animales , Tratamiento Basado en Trasplante de Células y Tejidos , Herpesvirus Humano 4/genética , Inmunoterapia Adoptiva , Células Madre Pluripotentes Inducidas/metabolismo , Linfoma/genética , Linfoma/terapia , Ratones , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T Citotóxicos , Proteínas de la Matriz Viral/genética
20.
Cancer Med ; 10(19): 6786-6794, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34477310

RESUMEN

Telomere length is maintained by the activation of telomerase, which causes continuous cell division and proliferation in many carcinomas. A catalytic reverse transcriptase protein (TERT) encoded by the TERT gene plays a critical role in the activation of telomerase. We performed a molecular and pathological analysis of the TERT against three different peripheral T-cell lymphoma (PTCL) subtypes: PTCL, not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and adult T-cell leukemia/lymphoma (ATLL). Immunohistochemical analysis demonstrated TERT expression in 31% of AITL, 11% of PTCL-NOS, and 5% of ATLL. Among them, AITL frequently showed high TERT expression with statistical significance. TERT promoter mutation analysis and genomic copy number evaluation were performed. TERT promoter mutation was observed in two cases of PTCL-NOS (2/40) and not in other PTCLs. Genome copy number amplification was detected in 33% of PTCL-NOS, 33% of AITL, and 50% of ATLL cases. We evaluated the relationship between the analyzed TERT genomic abnormalities and protein expression; however, no apparent relationship was observed. Furthermore, immunostaining showed TERT expression in the PTCL cytoplasm, suggesting the existence of mechanisms other than the maintenance of telomere length. Statistical analysis of the effect of TERT expression on the prognosis in PTCL cases revealed that TERT expression tended to have a poor prognosis in PTCL-NOS. Since TERT expression was not an independent factor in multivariate analysis, further research will be needed to clarify the poor prognosis of PTCL-NOS in TERT expression.


Asunto(s)
Inmunohistoquímica/métodos , Linfoma de Células T Periférico/genética , Telomerasa/metabolismo , Femenino , Humanos , Linfoma de Células T Periférico/mortalidad , Masculino , Análisis de Supervivencia
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