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1.
Stem Cells ; 38(1): 146-159, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31502731

RESUMO

Clinical-grade mesenchymal stromal cells (MSCs) can be expanded from bone marrow and adipose tissue to treat inflammatory diseases and degenerative disorders. However, the influence of their tissue of origin on their functional properties, including their immunosuppressive activity, remains unsolved. In this study, we produced paired bone marrow-derived mesenchymal stromal cell (BM-MSC) and adipose-derived stromal cell (ASC) batches from 14 healthy donors. We then compared them using transcriptomic, phenotypic, and functional analyses and validated our results on purified native MSCs to infer which differences were really endowed by tissue of origin. Cultured MSCs segregated together owing to their tissue of origin based on their gene expression profile analyzed using differential expression and weighted gene coexpression network analysis. This translated into distinct immune-related gene signatures, phenotypes, and functional cell interactions. Importantly, sorted native BM-MSCs and ASCs essentially displayed the same distinctive patterns than their in vitro-expanded counterparts. As a whole, ASCs exhibited an immune profile consistent with a stronger inhibition of immune response and a lower immunogenicity, supporting the use of adipose tissue as a valuable source for clinical applications.

2.
Epigenomics ; 12(2): 157-169, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31849241

RESUMO

The tumor microenvironment (TME) plays a central role in tumor development and drug resistance. Within TME, the stromal cell subset, called cancer-associated fibroblasts, is a heterogeneous population originating from poorly characterized precursors. Since cancer-associated fibroblasts do not acquire somatic mutations, other mechanisms like epigenetic regulation, could be involved in the development of these cells and in the acquisition of tumor supportive phenotypes. Moreover, such epigenetic modulations have been correlated to the emergence of an immunosuppressive microenvironment facilitating tumor evasion. These findings underline the need to deepen our knowledge on epigenetic mechanisms driving TME development and function, and to understand the impact of epigenetic drugs that could be used in future to target both tumor cells and their TME.

4.
Proc Natl Acad Sci U S A ; 116(27): 13490-13497, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31213547

RESUMO

Resident fibroblasts at sites of infection, chronic inflammation, or cancer undergo phenotypic and functional changes to support leukocyte migration and, in some cases, aggregation into tertiary lymphoid structures (TLS). The molecular programming that shapes these changes and the functional requirements of this population in TLS development are unclear. Here, we demonstrate that external triggers at mucosal sites are able to induce the progressive differentiation of a population of podoplanin (pdpn)-positive stromal cells into a network of immunofibroblasts that are able to support the earliest phases of TLS establishment. This program of events, that precedes lymphocyte infiltration in the tissue, is mediated by paracrine and autocrine signals mainly regulated by IL13. This initial fibroblast network is expanded and stabilized, once lymphocytes are recruited, by the local production of the cytokines IL22 and lymphotoxin. Interfering with this regulated program of events or depleting the immunofibroblasts in vivo results in abrogation of local pathology, demonstrating the functional role of immunofibroblasts in supporting TLS maintenance in the tissue and suggesting novel therapeutic targets in TLS-associated diseases.

5.
Immunol Lett ; 215: 12-18, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30844420

RESUMO

Stromal cells have been considered for a long time essentially as a structural component organizing tissue architecture, including those of secondary lymphoid organs. More recently, highly specialized stromal cell subsets were shown to differentially organize immune cell recruitment, survival, and differentiation within lymph nodes. In particular, mature B cells interact with different lymphoid stromal cell networks through bidirectional interactions involving cell-cell contact and soluble factors. Follicular lymphoma (FL) is the paradigm of a B-cell malignancy dependent on a lymphoid-like microenvironment supporting tumor cell growth, drug resistance, and clonal evolution. This review provides an overview of our current knowledge of lymphoid stromal cell heterogeneity and functions in normal B-cell activation. In addition, we also depict the dynamic and plasticity of FL cancer-associated fibroblasts, the mechanisms underlying their key role within FL permissive niches, and their potential as therapeutic targets in this still fatal malignancy.

6.
Br J Haematol ; 185(2): 240-253, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30767211

RESUMO

Chemotherapy plus rituximab has been the mainstay of treatment for follicular lymphoma (FL) for two decades but is associated with immunosuppression and relapse. In phase 2 studies, lenalidomide combined with rituximab (R2 ) has shown clinical synergy in front-line and relapsed/refractory FL. Here, we show that lenalidomide reactivated dysfunctional T and Natural Killer (NK) cells ex vivo from FL patients by enhancing proliferative capacity and T-helper cell type 1 (Th1) cytokine release. In combination with rituximab, lenalidomide improved antibody-dependent cellular cytotoxicity in sensitive and chemo-resistant FL cells, via a cereblon-dependent mechanism. While single-agent lenalidomide and rituximab increased formation of lytic NK cell immunological synapses with primary FL tumour cells, the combination was superior and correlated with enhanced cytotoxicity. Immunophenotyping of FL patient samples from a phase 3 trial revealed that R2 treatment increased circulating T- and NK-cell counts, while R-chemotherapy was associated with reduced cell numbers. Finally, using an in vitro model of myeloid differentiation, we demonstrated that lenalidomide caused a reversible arrest in neutrophil maturation that was distinct from a cytotoxic chemotherapeutic agent, which may help explain the lower rates of neutropenia observed with R2 versus R-chemotherapy. Taken together, we believe these data support a paradigm shift in the treatment of FL - moving from combination immunochemotherapy to chemotherapy-free immunotherapy.

7.
Clin Cancer Res ; 25(2): 735-746, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30348636

RESUMO

PURPOSE: Follicular lymphoma arises from a germinal center B-cell proliferation supported by a bidirectional crosstalk with tumor microenvironment, in particular with follicular helper T cells (Tfh). We explored the relation that exists between the differentiation arrest of follicular lymphoma cells and loss-of-function of CREBBP acetyltransferase.Experimental Design: The study used human primary cells obtained from either follicular lymphoma tumors characterized for somatic mutations, or inflamed tonsils for normal germinal center B cells. Transcriptome and functional analyses were done to decipher the B- and T-cell crosstalk. Responses were assessed by flow cytometry and molecular biology including ChIP-qPCR approaches. RESULTS: Conversely to normal B cells, follicular lymphoma cells are unable to upregulate the transcription repressor, PRDM1, required for plasma cell differentiation. This defect occurs although the follicular lymphoma microenvironment is enriched in the potent inducer of PRDM1 and IL21, highly produced by Tfhs. In follicular lymphoma carrying CREBBP loss-of-function mutations, we found a lack of IL21-mediated PRDM1 response associated with an abnormal increased enrichment of the BCL6 protein repressor in PRDM1 gene. Moreover, in these follicular lymphoma cells, pan-HDAC inhibitor, vorinostat, restored their PRDM1 response to IL21 by lowering BCL6 bound to PRDM1. This finding was reinforced by our exploration of patients with follicular lymphoma treated with another pan-HDAC inhibitor. Patients showed an increase of plasma cell identity genes, mainly PRDM1 and XBP1, which underline the progression of follicular lymphoma B cells in the differentiation process. CONCLUSIONS: Our data uncover a new mechanism by which pan-HDAC inhibitors may act positively to treat patients with follicular lymphoma through the induction of the expression of plasma cell genes.

8.
Nat Commun ; 9(1): 4775, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429474

RESUMO

BRAF inhibitors target the BRAF-V600E/K mutated kinase, the driver mutation found in 50% of cutaneous melanoma. They give unprecedented anti-tumor responses but acquisition of resistance ultimately limits their clinical benefit. The master regulators driving the expression of resistance-genes remain poorly understood. Here, we demonstrate that the Aryl hydrocarbon Receptor (AhR) transcription factor is constitutively activated in a subset of melanoma cells, promoting the dedifferentiation of melanoma cells and the expression of BRAFi-resistance genes. Typically, under BRAFi pressure, death of BRAFi-sensitive cells leads to an enrichment of a small subpopulation of AhR-activated and BRAFi-persister cells, responsible for relapse. Also, differentiated and BRAFi-sensitive cells can be redirected towards an AhR-dependent resistant program using AhR agonists. We thus identify Resveratrol, a clinically compatible AhR-antagonist that abrogates deleterious AhR sustained-activation. Combined with BRAFi, Resveratrol reduces the number of BRAFi-resistant cells and delays tumor growth. We thus propose AhR-impairment as a strategy to overcome melanoma resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Melanoma/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Receptores de Hidrocarboneto Arílico/genética , Neoplasias Cutâneas/genética , Animais , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Imidazóis/farmacologia , Células MCF-7 , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Camundongos SCID , Simulação de Acoplamento Molecular , Mutação , Oximas/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Fatores de Transcrição , Carga Tumoral/efeitos dos fármacos , Vemurafenib/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Blood Adv ; 2(15): 1889-1900, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30087107

RESUMO

A better characterization of T-cell subsets in the microenvironment of classical Hodgkin lymphoma (cHL) would help to develop immunotherapies. Using multicolor flow cytometry, we identified in 6 of 43 cHL tissue samples a previously unrecognized subset of CD8 T cells coexpressing CXCR5 and inducible T-cell costimulator (ICOS) molecules (CD8CXCR5+ICOS+). These cells shared phenotypic features with follicular helper T (TFH) cells including low CCR7 expression together with high expression of B-cell lymphoma-6, programmed cell death 1, B and T lymphocyte attenuator, CD200, and OX40. They had deficient cytotoxicity, low interferon-γ secretion, and common functional properties with intratumoral CD4+ TFH cells, such as production of interleukin-4 (IL-4), IL-21, CXCL13, and capacity to sustain B cells. Gene profiling analysis showed a significant similarity between the signatures of CD8CXCR5+ICOS+ T cells and CD4+ TFH cells. Benign lymphadenitis tissues (n = 8) were devoid of CD8CXCR5+ICOS+ cells. Among the 35 B-cell lymphoma tissues analyzed, including follicular lymphomas (n = 13), diffuse large cell lymphomas (n = 12), marginal zone lymphomas (MZLs; n = 3), mantle cell lymphomas (n = 3), and chronic lymphocytic leukemias (n = 4), only 1 MZL sample contained CD8CXCR5+ICOS+ cells. Lymphoma tumors with CD8CXCR5+ICOS+ cells shared common histopathological features including residual germinal centers, and contained high amounts of activated CD8CXCR5-ICOS+ cells. These data demonstrate a CD8 T-cell differentiation pathway leading to the acquisition of some TFH similarities. They suggest a particular immunoediting process with global CD8 activation acting mainly, but not exclusively, in HL tumors.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Regulação Neoplásica da Expressão Gênica , Doença de Hodgkin/metabolismo , Proteína Coestimuladora de Linfócitos T Induzíveis/biossíntese , Proteínas de Neoplasias/biossíntese , Receptores CXCR5/biossíntese , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular , Citocinas/metabolismo , Feminino , Doença de Hodgkin/patologia , Humanos , Masculino
10.
Blood ; 132(14): 1486-1494, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30068505

RESUMO

Obinutuzumab is a type II anti-CD20 monoclonal antibody that enhances antibody-dependent cellular cytotoxicity better than rituximab. Given promising results with lenalidomide and rituximab, this phase 1b study assessed the safety and efficacy of lenalidomide combined with obinutuzumab (GALEN). Patients age ≥18 years with relapsed or refractory (R/R) follicular lymphoma (FL) after rituximab-containing therapy received escalating doses (10 [n = 7], 15 [n = 3], 20 [n = 6], and 25 mg [n = 3]) of daily oral lenalidomide on days 1 to 21 of cycle 1 and on days 2 to 22 of cycles 2 to 6 (28-day cycles). Obinutuzumab 1000 mg IV was administered on days 8, 15, and 22 (cycle 1) and on day 1 (cycles 2-6). Dose was escalated in a 3 + 3 design based on dose-limiting toxicity (DLT) during cycle 1 to establish the maximum tolerated dose (MTD). We observed 164 adverse events (AEs), of which 139 were grade 1/2. The most common AEs were constipation (52.6%), neutropenia (47.4%), and asthenia (36.8%); 64.3% (9 of 14) of the grade 3/4 AEs were neutropenia/neutrophil decrease, but without any febrile neutropenia. Four DLTs occurred in 2 patients, all deemed unrelated to treatment. MTD was not reached. Twelve patients (63.2%) responded: 8 complete, 3 unconfirmed complete, and 1 partial response. Oral lenalidomide plus obinutuzumab is well tolerated and effective in R/R FL. The recommended dose of lenalidomide was established at 20 mg based on the risk of grade 3/4 neutropenia from cycle 2. This trial was registered at www.clinicaltrials.gov as #NCT01582776.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade
11.
Artigo em Inglês | MEDLINE | ID: mdl-30003080

RESUMO

Fibroblastic reticular cells (FRCs), the T-cell zone stromal cell subtype in the lymph nodes, create a scaffold for adhesion and migration of immune cells, thus allowing them to communicate. Although known to be important for the initiation of immune responses, studies about FRCs and their interactions have been impeded because FRCs are limited in availability and lose their function upon culture expansion. To circumvent these limitations, stromal cell precursors can be mechanotranduced to form mature FRCs. Here, we used a library of designed surface topographies to trigger FRC differentiation from tonsil-derived stromal cells (TSCs). Undifferentiated TSCs were seeded on a TopoChip containing 2176 different topographies in culture medium without differentiation factors, then monitored cell morphology and the levels of ICAM-1, a marker of FRC differentiation. We identified 112 and 72 surfaces that upregulated and downregulated, respectively, ICAM-1 expression. By monitoring cell morphology, and expression of the FRC differentiation marker ICAM-1 via image analysis and machine learning, we discovered correlations between ICAM-1 expression, cell shape and design of surface topographies and confirmed our findings by using flow cytometry. Our findings confirmed that TSCs are mechano-responsive cells and identified particular topographies that can be used to improve FRC differentiation protocols.

12.
Eur Respir J ; 52(2)2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29946009

RESUMO

Exaggerated release of neutrophil extracellular traps (NETs) along with decreased NET clearance and inability to remove apoptotic cells (efferocytosis) may contribute to sustained inflammation in acute respiratory distress syndrome (ARDS). Recent studies in experimental models of ARDS have revealed the crosstalk between AMP-activated protein kinase (AMPK) and high-mobility group box 1 (HMGB1), which may contribute to effectiveness of efferocytosis, thereby reducing inflammation and ARDS severity.We investigated neutrophil and NET clearance by macrophages from control and ARDS patients and examined how bronchoalveolar lavage (BAL) fluid from control and ARDS patients could affect NET formation and efferocytosis. Metformin (an AMPK activator) and neutralising antibody against HMGB1 were applied to improve efferocytosis and NET clearance.Neutrophils from ARDS patients showed significantly reduced apoptosis. Conversely, NET formation was significantly enhanced in ARDS patients. Exposure of neutrophils to ARDS BAL fluid promoted NET production, while control BAL fluid had no effect. Macrophage engulfment of NETs and apoptotic neutrophils was diminished in ARDS patients. Notably, activation of AMPK in macrophages or neutralisation of HMGB1 in BAL fluid improved efferocytosis and NET clearance.In conclusion, restoration of AMPK activity with metformin or specific neutralisation of HMGB1 in BAL fluid represent promising therapeutic strategies to decrease sustained lung inflammation during ARDS.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Armadilhas Extracelulares/metabolismo , Proteína HMGB1/metabolismo , Macrófagos/citologia , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Idoso , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Fagocitose , Pneumonia/metabolismo , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia
13.
Mol Cancer Ther ; 17(8): 1739-1751, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29743205

RESUMO

CD47, an ubiquitously expressed innate immune checkpoint receptor that serves as a universal "don't eat me" signal of phagocytosis, is often upregulated by hematologic and solid cancers to evade immune surveillance. Development of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hemotoxicity including anemia. To overcome such liabilities, we have developed a fully human bispecific antibody, NI-1701, designed to coengage CD47 and CD19 selectively on B cells. NI-1701 demonstrates favorable elimination kinetics with no deleterious effects seen on hematologic parameters following single or multiple administrations to nonhuman primates. Potent in vitro and in vivo activity is induced by NI-1701 to kill cancer cells across a plethora of B-cell malignancies and control tumor growth in xenograft mouse models. The mechanism affording maximal tumor growth inhibition by NI-1701 is dependent on the coengagement of CD47/CD19 on B cells inducing potent antibody-dependent cellular phagocytosis of the targeted cells. NI-1701-induced control of tumor growth in immunodeficient NOD/SCID mice was more effective than that achieved with the anti-CD20 targeted antibody, rituximab. Interestingly, a synergistic effect was seen when tumor-implanted mice were coadministered NI-1701 and rituximab leading to significantly improved tumor growth inhibition and regression in some animals. We describe herein, a novel bispecific antibody approach aimed at sensitizing B cells to become more readily phagocytosed and eliminated thus offering an alternative or adjunct therapeutic option to patients with B-cell malignancies refractory/resistant to anti-CD20-targeted therapy. Mol Cancer Ther; 17(8); 1739-51. ©2018 AACR.


Assuntos
Anticorpos Biespecíficos/genética , Leucemia/genética , Leucemia/terapia , Linfoma de Células B/genética , Linfoma de Células B/terapia , Animais , Antígenos CD19 , Antígeno CD47 , Humanos , Leucemia/patologia , Linfoma de Células B/patologia , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Curr Opin Hematol ; 25(4): 335-345, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29746265

RESUMO

PURPOSE OF REVIEW: In addition to the recent progresses in the description of the genetic landscape of B-cell non-Hodgkin's lymphomas, tumor microenvironment has progressively emerged as a central determinant of early lymphomagenesis, subclonal evolution, drug resistance, and late progression/transformation. The purpose of this review is to outline the most recent findings regarding malignant B-cell niche composition and organization supporting direct and indirect tumor-promoting functions of lymphoma microenvironment. RECENT FINDINGS: Lymphoma supportive niche integrates a dynamic and orchestrated network of immune and stromal cell subsets producing, with a high level of spatial and kinetic heterogeneity, extracellular and membrane factors regulating tumor migration, survival, proliferation, immune escape, as well as tumor microarchitecture, and mechanical constraints. Some recent insights have improved our understanding of these various components of lymphoma microenvironment, taking into account the mechanisms underlying the coevolution of malignant and nonmalignant cells within the tumor niche. SUMMARY: Deciphering tumor niche characteristics, functions, and origin could offer new therapeutic opportunities through the targeting of pivotal cellular and molecular components of the supportive microenvironment, favoring immune cell reactivation and infiltration, and/or limiting tumor retention within this protective niche.


Assuntos
Transformação Celular Neoplásica , Resistencia a Medicamentos Antineoplásicos/imunologia , Linfoma de Células B/metabolismo , Microambiente Tumoral/imunologia , Animais , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Humanos , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Linfoma de Células B/terapia , Células Estromais/imunologia , Células Estromais/metabolismo , Células Estromais/patologia
15.
Oncoimmunology ; 7(4): e1409322, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29632722

RESUMO

Obinutuzumab (OBZ) shows stronger antibody-dependent cell cytotoxicity (ADCC) compared to rituximab and improved clinical activity for treating certain CD20+ neoplasia. However, the efficacy of monoclonal antibody (mAb) as a monotherapy is limited. Natural Killer (NK) cells are mediators of ADCC. Hematological cancer patients possess antitumor NK cells that are unable to control disease, possibly because they are dysfunctional. The immunomodulatory drug lenalidomide (LEN) could be a treatment to restore exhausted NK cell cytotoxic functions. The clinical trial GALEN is a Phase Ib/II study of OBZ combined with LEN for the treatment of relapsed/refractory follicular and aggressive (DLBCL and MCL) B-cell Lymphoma. During treatment, we analyzed specific aspects of NK cell biology. Treatment reversed the immature NK phenotype of patients and increased expression of NK activating receptors. Inhibitory receptors were either unchanged or decreased. There was a strong NK response at the end of the 1st cycle: NK number and intracellular granzyme B (GrzB) expression decreased, degranulation increased and NK responded better to allogeneic target challenge. Moreover, the interaction of NK cells with B cell targets, measured by trogocytosis, decreased during treatment. At the end of treatment, when target cells had been wiped out, the proportion of reactive NK cells (CD69+, CD45RARO+, CD107a+, CD19+) strongly decreased. Because all patients received LEN and OBZ, it was uncertain which drug was responsible of our observations, or even if a combination of both products was necessary for the described effects on this lymphocyte lineage.

17.
Lancet Oncol ; 19(4): 549-561, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29475724

RESUMO

BACKGROUND: Patients with follicular lymphoma have heterogeneous outcomes. Predictor models to distinguish, at diagnosis, between patients at high and low risk of progression are needed. The objective of this study was to use gene-expression profiling data to build and validate a predictive model of outcome for patients treated in the rituximab era. METHODS: A training set of fresh-frozen tumour biopsies was prospectively obtained from 160 untreated patients with high-tumour-burden follicular lymphoma enrolled in the phase 3 randomised PRIMA trial, in which rituximab maintenance was evaluated after rituximab plus chemotherapy induction (median follow-up 6·6 years [IQR 6·0-7·0]). RNA of sufficient quality was obtained for 149 of 160 cases, and Affymetrix U133 Plus 2.0 microarrays were used for gene-expression profiling. We did a multivariate Cox regression analysis to identify genes with expression levels associated with progression-free survival independently of maintenance treatment in a subgroup of 134 randomised patients. Expression levels from 95 curated genes were then determined by digital expression profiling (NanoString technology) in 53 formalin-fixed paraffin-embedded samples of the training set to compare the technical reproducibility of expression levels for each gene between technologies. Genes with high correlation (>0·75) were included in an L2-penalised Cox model adjusted on rituximab maintenance to build a predictive score for progression-free survival. The model was validated using NanoString technology to digitally quantify gene expression in 488 formalin-fixed, paraffin-embedded samples from three independent international patient cohorts from the PRIMA trial (n=178; distinct from the training cohort), the University of Iowa/Mayo Clinic Lymphoma SPORE project (n=201), and the Barcelona Hospital Clinic (n=109). All tissue samples consisted of pretreatment diagnostic biopsies and were confirmed as follicular lymphoma grade 1-3a. The patients were all treated with regimens containing rituximab and chemotherapy, possibly followed by either rituximab maintenance or ibritumomab-tiuxetan consolidation. We determined an optimum threshold on the score to predict patients at low risk and high risk of progression. The model, including the multigene score and the threshold, was initially evaluated in the three validation cohorts separately. The sensitivity and specificity of the score for the prediction of the risk of lymphoma progression at 2 years were assessed on the combined validation cohorts. FINDINGS: In the training cohort, the expression levels of 395 genes were associated with a risk of progression. 23 genes reflecting both B-cell biology and tumour microenvironment with correlation coefficients greater than 0·75 between the two technologies and sample types were retained to build a predictive model that identified a population at an increased risk of progression (p<0·0001). In a multivariate Cox model for progression-free survival adjusted on rituximab maintenance treatment and Follicular Lymphoma International Prognostic Index 1 (FLIPI-1) score, this predictor independently predicted progression (adjusted hazard ratio [aHR] of the high-risk group compared with the low-risk group 3·68, 95% CI 2·19-6·17 [p<0·0001]). The 5-year progression-free survival was 26% (95% CI 16-43) in the high-risk group and 73% (64-83) in the low-risk group. The predictor performances were confirmed in each of the individual validation cohorts (aHR comparing high-risk to low-risk groups 2·57 [95% CI 1·65-4·01] in cohort 1; 2·12 [1·32-3·39] in cohort 2; and 2·11 [1·01-4·41] in cohort 3). In the combined validation cohort, the median progression-free survival was 3·1 years (95% CI 2·4-4·8) in the high-risk group and 10·8 years (10·1-not reached) in the low-risk group (p<0·0001). The risk of lymphoma progression at 2 years was 38% (95% CI 29-46) in the high-risk group and 19% (15-24) in the low-risk group. In a multivariate analysis, the score predicted progression-free survival independently of anti-CD20 maintenance treatment and of the FLIPI score (aHR for the combined cohort 2·30, 95% CI 1·72-3·07). INTERPRETATION: We developed and validated a robust 23-gene expression-based predictor of progression-free survival that is applicable to routinely available formalin-fixed, paraffin-embedded tumour biopsies from patients with follicular lymphoma at time of diagnosis. Applying this score could allow individualised therapy for patients according to their risk category. FUNDING: Roche, SIRIC Lyric, LYSARC, National Institutes of Health, the Henry J Predolin Foundation, and the Spanish Plan Nacional de Investigacion.


Assuntos
Perfilação da Expressão Gênica , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/genética , RNA Neoplásico/análise , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Internacionalidade , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Medição de Risco/métodos , Rituximab/administração & dosagem
19.
Bull Cancer ; 105 Suppl 1: S80-S91, 2018 Dec.
Artigo em Francês | MEDLINE | ID: mdl-30595202

RESUMO

PREDICTIVE BIOMARKERS OF RESPONSE TO IMMUNE CHECKPOINT INHIBITORS: PD-1 checkpoint inhibitors are becoming the reference treatment for several types of cancers. Many patients show remarkable efficacy and low toxicity. However, some patients have a better outcome than others with PD-1 checkpoint inhibitors. So, it is crucial to identify biomarkers of response. We review here the available data of several potential biomarkers of efficacy. The expression of PD-L1, detected by immunohistochemistry on tumor cells and immune cells is a good predictive biomarker of response for some cancers; however, this method is not standardized, and there are different antibodies, different cut-off values, and different targets (tumor or microenvironment). Moreover, the expression of PD-L1 is dynamic and heterogeneous within the tumor: expression is discordant between primary tumor and metastasis or between biopsy and surgical specimen. Peripheral blood lymphocytes also can be informative, especially the baseline neutrophil to lymphocyte ratio which is easy to measure in daily practice. High rate of neoantigens is also associated with improved response. Therefore, mutation burden can be predictive of response and this explains why tumors with microsatellites instability have an enhanced response. Similarly, genetic signatures are linked with resistance or response to treatment. Gut microbiota is associated with improved antitumor immune response although the underlying mechanism is not well understood so far. Lastly, it seems that cytokines, mediators of immunity may play a role in the response to immunotherapy and so, constitute an interesting biomarker. Several potential biomarkers are identified but none is prospectively validated so far.


Assuntos
Biomarcadores Tumorais , Antígeno CTLA-4/antagonistas & inibidores , Imunoterapia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno CTLA-4/metabolismo , Ensaios Clínicos como Assunto , Citocinas/fisiologia , Humanos , Contagem de Leucócitos , Contagem de Linfócitos , Microbiota , Instabilidade de Microssatélites , Neoplasias/sangue , Neoplasias/genética , Neutrófilos/citologia , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo
20.
Hematology Am Soc Hematol Educ Program ; 2017(1): 610-617, 2017 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-29222311

RESUMO

Recent progress in next-generation sequencing strategies has revealed the genetic landscape of B-cell non-Hodgkin lymphoma, but the tumor microenvironment is increasingly recognized as crucial to sustaining malignant B-cell survival and growth, subclonal evolution, and drug resistance. The tumor niche is made up of a dynamic and organized network of strongly heterogeneous immune and stromal cell subsets characterized by specific phenotypic, transcriptomic, and functional features. Nonmalignant cell recruitment and plasticity are dictated by lymphoma B cells, which convert their surrounding microenvironment into a supportive niche. In addition, they are also influenced by the crosstalk between the various components of this niche. In agreement with this, the B-cell lymphoma subtype is a key determinant of the organization of the tumor niche, but genetic alteration patterns, tumor localization, stage of the disease, and treatment strategy may also modulate its composition and activity. Moreover, the complex set of bidirectional interactions between B cells and their microenvironment has been proposed as a promising therapeutic target with the aim of reinforcing antitumor immunity and/or of abbrogating the lymphoma-promoting signals delivered by the tumor niche.


Assuntos
Comunicação Celular/imunologia , Linfoma de Células B , Transdução de Sinais/imunologia , Microambiente Tumoral/imunologia , Animais , Humanos , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Linfoma de Células B/terapia
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