118 research outputs found
âStealthâ tumors: Breast cancer cells shun NK-cells anti-tumor immunity
Breast cancers (BCs) comprise heterogeneous subtypes of various prognoses. An active anti-tumor immune profile usually correlated with a better survival. Two current major challenges of BC research are to understand the inter-relations between BC and anti-tumor immunity, and to identify candidates whose targeting would contribute to enhance anti-tumor efficiency
CpG-ODN-induced sustained expression of BTLA mediating selective inhibition of human B cells
BTLA (B- and T-lymphocyte attenuator) is a prominent co-receptor that is structurally and functionally related to CTLA-4 and PD-1. In T cells, BTLA inhibits TCR-mediated activation. In B cells, roles and functions of BTLA are still poorly understood and have never been studied in the context of B cells activated by CpG via TLR9. In this study, we evaluated the expression of BTLA depending on activation and differentiation of human B cell subsets in peripheral blood and lymph nodes. Stimulation with CpG upregulated BTLA, but not its ligand: herpes virus entry mediator (HVEM), on B cells in vitro and sustained its expression in vivo in melanoma patients after vaccination. Upon ligation with HVEM, BTLA inhibited CpG-mediated B cell functions (proliferation, cytokine production, and upregulation of co-stimulatory molecules), which was reversed by blocking BTLA/HVEM interactions. Interestingly, chemokine secretion (IL-8 and MIP1ÎČ) was not affected by BTLA/HVEM ligation, suggesting that BTLA-mediated inhibition is selective for some but not all B cell functions. We conclude that BTLA is an important immune checkpoint for B cells, as similarly known for T cell
Contiguous follicular lymphoma and follicular lymphoma in situ harboring N-glycosylated sites
International audienceFollicular lymphoma in situ (FLIS) is composed of a clonal B-cell population harboring the typical t(14;18) hallmark of follicular lymphoma (FL), forming unconventional BCL2 Bright CD10 + cell foci in an otherwise normal reactive lymph node (LN). The diagnosis of FLIS is made on the fortuitous discovery of unconventional BCL2 Bright CD10 + cell foci. 1 Several studies recently demonstrated that FLIS are already advanced precursors in follicular lymphomagene-sis, but not necessarily committed to malignant transformation. 2,3 However, the relationship between FLIS and FL still remains unclear, as only a minority (<5%) of FLIS patients eventually develop FL. This is in line with the usually indolent progression of the disease, and the genomic instability observed in FLIS cells, which can engage FL precursor cells either in an evolutionary malignant process, or to an evolutionary dead end. 4 We report the case of a 35-year old male patient who presented with a cervical adenopathy. Histological examination of the excised LN displayed an altered architecture suggestive of FL, consisting of high number of monomorphic large follicles, uniformly spread in the cortical and medullary areas. Most follicles contained a predominant population of small cleaved cells with scant macrophages and mitoses. The mantle zone was reduced or absent. However, in a minor cortical area, a few follicles showed features mimicking residual classical germ cells (GC), including a smaller size, higher cell polymorphism, and a preserved mantle zone (Figure 1A). The BCL2 immunostaining (clone 100) was negative in follicles displaying a typical FL pattern. In contrast, follicles located in the pseudo-residual area were BCL2bright, i.e. more strongly stained than the surrounding mantle zone and reactive T cells (Figure 1B). Most follicles were only slightly positive for Ki67 (Online Supplementary Figure S1A). Both BCL2 â and BCL2 + follicles were CD10 positive (Online Supplementary Figure S1B) and contained a BCL2/JH break-point evidenced by fluorescence in situ hybridization (FISH) (Figure 1C). Taken together these results suggested the diagnosis of simultaneous occurrence of BCL2 â FL (grade I/II) and of BCL2 + FLIS in the same LN. We decided to further analyze those two lesions independently, and performed macrodissection in order to proceed with individual molecular analyses when required. Sanger sequenc-ing revealed that both FLIS and FL shared the same BCL2/JH sequence at the t(14;18)+ breakpoint, and thus originated from the same clone (Figure 1D). We tested two other anti-BCL2 antibodies (E17, SP66) directed against other epitopes, but the staining remained BCL2-in the FL area of the LN, similar to the anti-BCL2 antibody (clone 100) staining (Figure 1E and F). We thus sequenced exons 1 to 3 of the BCL2 gene (B-cell CLL/lym-phoma 2, NG_009361.1). Punctual mutations, resulting in amino acid substitutions, were found in the FL component (Online Supplementary Table S1), and were indeed located in the targeted aa41 to aa54 epitope of clone 100 (mutation
Kinome expression profiling and prognosis of basal breast cancers
<p>Abstract</p> <p>Background</p> <p>Basal breast cancers (BCs) represent ~15% of BCs. Although overall poor, prognosis is heterogeneous. Identification of good- <it>versus </it>poor-prognosis patients is difficult or impossible using the standard histoclinical features and the recently defined prognostic gene expression signatures (GES). Kinases are often activated or overexpressed in cancers, and constitute targets for successful therapies. We sought to define a prognostic model of basal BCs based on kinome expression profiling.</p> <p>Methods</p> <p>DNA microarray-based gene expression and histoclinical data of 2515 early BCs from thirteen datasets were collected. We searched for a kinome-based GES associated with disease-free survival (DFS) in basal BCs of the learning set using a metagene-based approach. The signature was then tested in basal tumors of the independent validation set.</p> <p>Results</p> <p>A total of 591 samples were basal. We identified a 28-kinase metagene associated with DFS in the learning set (N = 73). This metagene was associated with immune response and particularly cytotoxic T-cell response. On multivariate analysis, a metagene-based predictor outperformed the classical prognostic factors, both in the learning and the validation (N = 518) sets, independently of the lymphocyte infiltrate. In the validation set, patients whose tumors overexpressed the metagene had a 78% 5-year DFS <it>versus </it>54% for other patients (p = 1.62E-4, log-rank test).</p> <p>Conclusions</p> <p>Based on kinome expression, we identified a predictor that separated basal BCs into two subgroups of different prognosis. Tumors associated with higher activation of cytotoxic tumor-infiltrative lymphocytes harbored a better prognosis. Such classification should help tailor the treatment and develop new therapies based on immune response manipulation.</p
Human Breast Tumor Cells Induce Self-Tolerance Mechanisms to Avoid NKG2D-Mediated and DNAM-Mediated NK Cell Recognition
Whole-genome/exome analysis of circulating tumor DNA and comparison to tumor genomics from patients with heavily pre-treated ovarian cancer: subset analysis of the PERMED-01 trial
IntroductionThe poor prognosis of ovarian carcinoma (OvC) is due to the advanced stage at diagnosis, a high risk of relapse after first-line therapies, and the lack of efficient treatments in the recurrence setting. Circulating tumor DNA (ctDNA) analysis is a promising tool to assess treatment-resistant OvC and may avoid iterative tissue biopsies. We aimed to evaluate the genomic profile of recurrent heavily pre-treated OvC.MethodsWe performed tumor panel-based sequencing as well as low-coverage whole-genome sequencing (LC-WGS) of tumor and plasma collected in patients with ovarian cancer included in the PERMED-01 trial. Whole-exome sequencing (WES) data of plasma samples were also analyzed and compared to mutation and copy number alteration (CNA) tumor profiles. The prognostic value [progression-free survival (PFS)] of these alterations was assessed in an exploratory analysis.ResultsTumor and plasma genomic analyses were done for 24 patients with heavily pretreated OvC [67% high-grade serous carcinoma (HGSC)]. Tumor mutation burden was low (median 2.04 mutations/Mb) and the most frequent mutated gene was TP53 (94% of HGSC). Tumor CNAs were frequent with a median of 50% of genome altered fraction. Plasma LC-WGS and WES detected ctDNA in 21/24 cases (88%) with a median tumor fraction of 12.7%. We observed a low correlation between plasma and tumor CNA profiles. However, this correlation was significant in cases with the highest circulating tumor fraction. Plasma genome altered fraction and plasma mutation burden (p = 0.011 and p = 0.041, respectively, log-rank tests) were associated with PFS.ConclusionsCombination of LC-WGS and WES can detect ctDNA in most pre-treated OvCs. Some ctDNA characteristics, such as genome altered fraction and plasma mutation burden, showed prognostic value. ctDNA assessment with LC-WGS may be a promising and non-expansive tool to evaluate disease evolution in this disease with high genomic instability.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT02342158, identifier NCT02342158
Etude des mécanismes immunologiques impliqués dans la perte de contrÎle de l'inflammation au cours des exacerbations de l'asthme sévÚre (données de l'étude ISEA, Induced Sputum In Exacerbation of Asthma)
La prĂ©valence des pathologies atopiques est en constante augmentation dans tous les pays industrialisĂ©s. Ces maladies occupent aujourd'hui la quatriĂšme place des maladies mondialement recensĂ©es par l'OMS. D'un point de vue immunopathologique, les Ă©tudes rĂ©alisĂ©es au cours de ces 20 derniĂšres annĂ©es ont montrĂ© que les maladies atopiques impliquaient une activation des lymphocytes Th2, synthĂ©tisant de l'IL-4, IL-5 et IL-13. Ces cytokines sont responsables de l'activation et du recrutement d'autres cellules inflammatoires, notamment les Ă©osinophiles, et de la libĂ©ration de mĂ©diateurs de l'inflammation responsables de la contraction des muscles bronchiques, de la destruction des tissus environnants et de la sĂ©crĂ©tion de mucus, caractĂ©ristiques des symptĂŽmes allergiques. Pourtant plusieurs travaux suggĂšrent que cette inflammation, pertinente pour l'atopie et la prĂ©sence des Ă©osinophiles dans les tissus atteints, est insuffisante pour expliquer l'asthme. C'est cette problĂ©matique qui a orientĂ© les recherches menĂ©es au cours de ma thĂšse. Ainsi, nous avons montrĂ©, dans l'asthme, qu'Ă l'inflammation chronique de type Th2, Ă©tait associĂ©e une inflammation aiguĂ« Th1 avec production d'IFN- . Par ailleurs il a rĂ©cemment Ă©tĂ© montrĂ© que des lymphocytes T dits rĂ©gulateurs (Treg), producteurs d'IL-10 et/ou de TGF- et inducteurs de tolĂ©rance Ă©taient dĂ©ficitaires chez les sujets allergiques. Nous avons effectivement mis en Ă©vidence une diminution de cette population chez l'asthmatique en crise, et Ă©mis l'hypothĂšse que leur diminution pourrait rendre compte de l'activation chronique Th2 rencontrĂ©e chez l'atopique, et de l'augmentation Th1 aiguĂ« chez l'asthmatique. Le second projet a portĂ© sur l'Ă©tude de l'inflammation bronchique et pĂ©riphĂ©rique au cours du rejet chronique de greffe, la bronchiolite oblitĂ©rante (BO), qui est actuellement la principale complication Ă long terme de survie du patient. GrĂące au suivi des patients par expectoration induite, nous avons pu mettre en Ă©vidence que le poumon greffĂ© Ă©tait le site d'un phĂ©nomĂšne inflammatoire qui persistait tout au long de la vie du receveur, mĂȘme en l'absence de phĂ©nomĂšne de rejet ou d'infection, et que la BO Ă©tait associĂ©e Ă une augmentation de la proportion des Ă©osinophiles bronchiques. Nous avons ensuite investiguĂ© l'inflammation lymphocytaire T bronchique et pĂ©riphĂ©rique au cours des diffĂ©rents stades d'Ă©volution de la BO et Ă©tabli un profil Th1/Th2 mixte chez les BO de mauvais pronostic tandis que les BO stables prĂ©sentent un biais Th2. En revanche, le fait de dĂ©velopper une BO, quelque soit le stade Ă©volutif concernĂ©, est associĂ© Ă une augmentation trĂšs importante des populations T rĂ©gulatrices et de leurs cytokines respectives, suggĂ©rant que la BO pourrait ĂȘtre due Ă un excĂšs de tolĂ©rance plutĂŽt qu'Ă un vĂ©ritable rejet du greffon.AIX-MARSEILLE2-BU MĂ©d/Odontol. (130552103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF
The emerging role of the TGFÎČ tumor suppressor pathway in pancreatic cancer
International audienc
When breast cancer cells start to fend the educational process of NK cells off
International audienceThe notion of natural killer (NK)-cell education has recently emerged, and accumulating evidence indicates that the terminal differentiation of NK cells can be achieved in the periphery. This means that the proper function of these lymphocytes is dependent on their environment, opening a new door through which cancer cells can escape immunosurveillance
Les granules de stress, des acteurs émergents en cancérologie
International audienceCancer cells are submitted to numerous stresses during tumor development, such as hypoxia, lack of nutrient, oxidative stress, or mechanical constriction. A complex mechanism termed the integrated stress response (ISR) occurs allowing cell survival. This mechanism leads to the formation of membraneless cytoplasmic structures called stress granules. The hypothesis that these structures play a major role during tumorigenesis has recently emerged. Here, we describe the biological function of stress granules and of proteins that their formation. We also present the current evidences for their involvement in the development of tumors and in the tumor resistance to cancer drugs. Finally, we discuss the interest of targeting stress granule formation to enhance treatment efficiency in order to delay tumor progression.Les stress induits au sein des tumeurs en cours de dĂ©veloppement (hypoxie, stress oxydant, etc.) sont connus depuis de nombreuses annĂ©es. Cependant, lâimplication de la rĂ©ponse au stress dans le processus tumoral est un concept rĂ©cent. Les granules de stress (GS) sont des structures cytoplasmiques qui se forment Ă la suite dâune exposition Ă un stress et qui ont des effets cytoprotecteurs. De nombreuses donnĂ©es sont en faveur de lâimplication de ces granules dans lâĂ©volution tumorale et mĂ©tastatique, mais aussi dans le dĂ©veloppement de la chimiorĂ©sistance des tumeurs. Nous abordons dans cet article le rĂŽle particulier des granules de stress en cancĂ©rologie et, plus spĂ©cifiquement, celui des protĂ©ines qui contrĂŽlent leur formation
- âŠ