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2.
Nat Cancer ; 2024 Jun 28.
Article de Anglais | MEDLINE | ID: mdl-38942927

RÉSUMÉ

Multiple myeloma (MM) is a plasma cell malignancy of the bone marrow. Despite therapeutic advances, MM remains incurable, and better risk stratification as well as new therapies are therefore highly needed. The proteome of MM has not been systematically assessed before and holds the potential to uncover insight into disease biology and improved prognostication in addition to genetic and transcriptomic studies. Here we provide a comprehensive multiomics analysis including deep tandem mass tag-based quantitative global (phospho)proteomics, RNA sequencing, and nanopore DNA sequencing of 138 primary patient-derived plasma cell malignancies encompassing treatment-naive MM, plasma cell leukemia and the premalignancy monoclonal gammopathy of undetermined significance, as well as healthy controls. We found that the (phospho)proteome of malignant plasma cells are highly deregulated as compared with healthy plasma cells and is both defined by chromosomal alterations as well as posttranscriptional regulation. A prognostic protein signature was identified that is associated with aggressive disease independent of established risk factors in MM. Integration with functional genetics and single-cell RNA sequencing revealed general and genetic subtype-specific deregulated proteins and pathways in plasma cell malignancies that include potential targets for (immuno)therapies. Our study demonstrates the potential of proteogenomics in cancer and provides an easily accessible resource for investigating protein regulation and new therapeutic approaches in MM.

4.
Blood ; 143(13): 1269-1281, 2024 Mar 28.
Article de Anglais | MEDLINE | ID: mdl-38197505

RÉSUMÉ

ABSTRACT: Acute myeloid leukemia (AML) is a hematologic malignancy for which allogeneic hematopoietic cell transplantation (allo-HCT) often remains the only curative therapeutic approach. However, incapability of T cells to recognize and eliminate residual leukemia stem cells might lead to an insufficient graft-versus-leukemia (GVL) effect and relapse. Here, we performed single-cell RNA-sequencing (scRNA-seq) on bone marrow (BM) T lymphocytes and CD34+ cells of 6 patients with AML 100 days after allo-HCT to identify T-cell signatures associated with either imminent relapse (REL) or durable complete remission (CR). We observed a higher frequency of cytotoxic CD8+ effector and gamma delta (γδ) T cells in CR vs REL samples. Pseudotime and gene regulatory network analyses revealed that CR CD8+ T cells were more advanced in maturation and had a stronger cytotoxicity signature, whereas REL samples were characterized by inflammatory tumor necrosis factor/NF-κB signaling and an immunosuppressive milieu. We identified ADGRG1/GPR56 as a surface marker enriched in CR CD8+ T cells and confirmed in a CD33-directed chimeric antigen receptor T cell/AML coculture model that GPR56 becomes upregulated on T cells upon antigen encounter and elimination of AML cells. We show that GPR56 continuously increases at the protein level on CD8+ T cells after allo-HCT and confirm faster interferon gamma (IFN-γ) secretion upon re-exposure to matched, but not unmatched, recipient AML cells in the GPR56+ vs GPR56- CD8+ T-cell fraction. Together, our data provide a single-cell reference map of BM-derived T cells after allo-HCT and propose GPR56 expression dynamics as a surrogate for antigen encounter after allo-HCT.


Sujet(s)
Transplantation de cellules souches hématopoïétiques , Leucémie aigüe myéloïde , Humains , Moelle osseuse/anatomopathologie , Leucémie aigüe myéloïde/thérapie , Leucémie aigüe myéloïde/traitement médicamenteux , Lymphocytes T CD8+/anatomopathologie , Récidive
5.
J Clin Oncol ; 42(1): 26-37, 2024 Jan 01.
Article de Anglais | MEDLINE | ID: mdl-37753960

RÉSUMÉ

PURPOSE: The GMMG-CONCEPT trial investigated isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in transplant-eligible (TE) and transplant-noneligible (TNE) patients with newly diagnosed multiple myeloma (NDMM) with exclusively high-risk disease for whom prospective trials are limited, aiming to induce minimal residual disease (MRD) negativity. METHODS: This academic, investigator-initiated, multicenter, phase II trial enrolled patients with high-risk NDMM (HRNDMM) defined by mandatory International Staging System stage II/III combined with del17p, t(4;14), t(14;16), or more than three 1q21 copies as high-risk cytogenetic aberrations (HRCAs). Patients received Isa-KRd induction/consolidation and Isa-KR maintenance. TE patients received high-dose melphalan. TNE patients received two additional Isa-KRd cycles postinduction. This prespecified interim analysis (IA) reports the primary end point, MRD negativity (<10-5, next-generation flow), at the end of consolidation. The secondary end point was progression-free survival (PFS). RESULTS: Among 125 patients with HRNDMM (TE-intention-to-treat [ITT]-IA, 99; TNE-ITT, 26) of the IA population for the primary end point, the median age was 58 (TE-ITT-IA) and 74 (TNE-ITT) years. Del17p was the most common HRCA (TE, 44.4%; TNE, 42.3%); about one third of evaluable TE/TNE patients presented two or more HRCAs, respectively. The trial met its primary end point with MRD negativity rates after consolidation of 67.7% (TE) and 54.2% (TNE) of patients. Eighty-one of 99 TE-ITT-IA patients reached MRD negativity at any time point (81.8%). MRD negativity was sustained for ≥1 year in 62.6% of patients. With a median follow-up of 44 (TE) and 33 (TNE) months, median PFS was not reached in either arm. CONCLUSION: Isa-KRd effectively induces high rates of sustainable MRD negativity in the difficult-to-treat HRNDMM population, regardless of transplant status, translating into a median PFS that was not yet reached after 44/33 months.


Sujet(s)
Myélome multiple , Humains , Adulte d'âge moyen , Myélome multiple/thérapie , Lénalidomide/usage thérapeutique , Lénalidomide/pharmacologie , Études prospectives , Dexaméthasone/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/effets indésirables
6.
Trials ; 24(1): 591, 2023 Sep 15.
Article de Anglais | MEDLINE | ID: mdl-37715270

RÉSUMÉ

BACKGROUND: About 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile. METHODS: In this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m2 bidaily day one to day three, mitoxantrone 10mg/m2 days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization. The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders. Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 20 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument. CONCLUSION: Currently, there is no commonly accepted standard for salvage chemotherapy treatment. The objective of the salvage therapy is to reduce leukemic burden, achieve the best possible remission, and perform a hemopoietic stem-cell transplantation. Thus, in patients with FLT3-ITD mutation, the comparison of quizartinib with intensive salvage therapy versus chemotherapy alone appears as a logical consequence in terms of efficacy and safety. ETHICS AND DISSEMINATION: Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. TRIAL REGISTRATION: ClinicalTrials.gov NCT03989713; EudraCT Number: 2018-002675-17.


Sujet(s)
Leucémie aigüe myéloïde , Mitoxantrone , Humains , Mitoxantrone/effets indésirables , Leucémie aigüe myéloïde/traitement médicamenteux , Phénylurées/effets indésirables , Maladie chronique , Cytarabine/effets indésirables , Tyrosine kinase-3 de type fms/génétique
7.
Transplant Cell Ther ; 29(10): 609.e1-609.e6, 2023 Oct.
Article de Anglais | MEDLINE | ID: mdl-37348705

RÉSUMÉ

BCMA-specific chimeric-antigen receptor (CAR-) T cell therapy has led to high response rates and durable remissions in patients with relapsed refractory multiple myeloma. However, little data are available for patients after prior allogeneic stem cell transplantation (allo-SCT) in whom T cells are chimeric. In this study, we aimed to assess the safety and efficacy of patient-derived donor CAR-T therapy in myeloma patients with prior allo-SCT, particularly with regard to graft-versus-host disease (GVHD). We report a comprehensive clinical analysis of 3 patients who had previously undergone allo-SCT for high-risk myeloma and were treated with idecabtagene vicleucel (ide-cel) at our institution. Ide-cel was well tolerated, with no clinically relevant immune effector cell-associated neurotoxicity syndrome or cytokine release syndrome observed in any patient. Importantly, no new GVHD was observed, even though all patients had a history of GVHD. All patients responded to treatment with at least a very good partial remission. Two patients relapsed within 6 months, and 1 patient was still in stringent complete remission at the time of this report. Our findings demonstrate that treatment with ide-cel is feasible, very well tolerated, and effective in patients with relapsed/refractory multiple myeloma after prior allo-SCT.

8.
Front Oncol ; 13: 1078725, 2023.
Article de Anglais | MEDLINE | ID: mdl-37152008

RÉSUMÉ

Introduction: Infections are a leading cause of morbidity and mortality in patients with multiple myeloma (MM). Methods: To examine the effects of modern second-generation novel agent therapy on immune cell subsets, in particular CD4+-T-cells, and infectious complications in patients with relapsed/refractory MM (RRMM), we conducted a prospective cohort study in 112 RRMM patients. Results: Substantially decreased CD4+-T-cells <200/µl before initiation of relapse therapy were detected in 27.7% of patients and were associated with a higher number of previous lines of therapy. Relapse therapy with carfilzomib or pomalidomide showed a significant further decrease of CD4+-T-cells. All novel agents led to a significant decrease of B-cell counts. Overall, infections were frequent with 21.3% of patients requiring antibacterial therapy within the first 3 months of relapse therapy, 5.6% requiring hospitalization. However, in the setting of standard antimicrobial prophylaxis in RRMM patients with very low CD4+-T-cells, no significant association of CD4+T-cell count and an increased risk of infection could be detected. Discussion: Our findings imply that reduced CD4+-T-cell numbers and infections are common in patients with RRMM. We also demonstrate an association with the number of previous therapies and certain substances suggesting an increased need for personalized prophylaxis strategies for opportunistic infections in this patient cohort.

9.
Cell Stem Cell ; 30(5): 706-721.e8, 2023 05 04.
Article de Anglais | MEDLINE | ID: mdl-37098346

RÉSUMÉ

Inter-patient variability and the similarity of healthy and leukemic stem cells (LSCs) have impeded the characterization of LSCs in acute myeloid leukemia (AML) and their differentiation landscape. Here, we introduce CloneTracer, a novel method that adds clonal resolution to single-cell RNA-seq datasets. Applied to samples from 19 AML patients, CloneTracer revealed routes of leukemic differentiation. Although residual healthy and preleukemic cells dominated the dormant stem cell compartment, active LSCs resembled their healthy counterpart and retained erythroid capacity. By contrast, downstream myeloid progenitors constituted a highly aberrant, disease-defining compartment: their gene expression and differentiation state affected both the chemotherapy response and leukemia's ability to differentiate into transcriptomically normal monocytes. Finally, we demonstrated the potential of CloneTracer to identify surface markers misregulated specifically in leukemic cells. Taken together, CloneTracer reveals a differentiation landscape that mimics its healthy counterpart and may determine biology and therapy response in AML.


Sujet(s)
Leucémie aigüe myéloïde , Multi-omique , Humains , Leucémie aigüe myéloïde/génétique , Différenciation cellulaire , Cellules souches tumorales/métabolisme
10.
Cancer Discov ; 13(6): 1408-1427, 2023 06 02.
Article de Anglais | MEDLINE | ID: mdl-36892565

RÉSUMÉ

The BCL2 inhibitor venetoclax (VEN) in combination with azacitidine (5-AZA) is currently transforming acute myeloid leukemia (AML) therapy. However, there is a lack of clinically relevant biomarkers that predict response to 5-AZA/VEN. Here, we integrated transcriptomic, proteomic, functional, and clinical data to identify predictors of 5-AZA/VEN response. Although cultured monocytic AML cells displayed upfront resistance, monocytic differentiation was not clinically predictive in our patient cohort. We identified leukemic stem cells (LSC) as primary targets of 5-AZA/VEN whose elimination determined the therapy outcome. LSCs of 5-AZA/VEN-refractory patients displayed perturbed apoptotic dependencies. We developed and validated a flow cytometry-based "Mediators of apoptosis combinatorial score" (MAC-Score) linking the ratio of protein expression of BCL2, BCL-xL, and MCL1 in LSCs. MAC scoring predicts initial response with a positive predictive value of more than 97% associated with increased event-free survival. In summary, combinatorial levels of BCL2 family members in AML-LSCs are a key denominator of response, and MAC scoring reliably predicts patient response to 5-AZA/VEN. SIGNIFICANCE: Venetoclax/azacitidine treatment has become an alternative to standard chemotherapy for patients with AML. However, prediction of response to treatment is hampered by the lack of clinically useful biomarkers. Here, we present easy-to-implement MAC scoring in LSCs as a novel strategy to predict treatment response and facilitate clinical decision-making. This article is highlighted in the In This Issue feature, p. 1275.


Sujet(s)
Leucémie aigüe myéloïde , Protéomique , Humains , Protéines proto-oncogènes c-bcl-2/génétique , Protéines proto-oncogènes c-bcl-2/métabolisme , Leucémie aigüe myéloïde/traitement médicamenteux , Leucémie aigüe myéloïde/génétique , Composés hétérocycliques bicycliques/pharmacologie , Composés hétérocycliques bicycliques/usage thérapeutique , Azacitidine/pharmacologie , Azacitidine/usage thérapeutique , Cellules souches/métabolisme , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique
12.
J Immunother Cancer ; 10(10)2022 10.
Article de Anglais | MEDLINE | ID: mdl-36252999

RÉSUMÉ

Multiple myeloma (MM) is a hematological malignancy originating from malignant and clonally expanding plasma cells. MM can be molecularly stratified, and its clonal evolution deciphered based on the Ig heavy and light chains of the respective malignant plasma cell clone. Of all MM subtypes, IgE type MM accounts for only <0.1% of cases and is associated with an aggressive clinical course and consequentially dismal prognosis. In such malignancies, adoptive transfer of autologous lymphocytes specifically targeting presented (neo)epitopes encoded by either somatically mutated or specifically overexpressed genes has resulted in substantial objective clinical regressions even in relapsed/refractory disease. However, there are no data on the genetic and immunological characteristics of this rare and aggressive entity. Here, we comprehensively profiled IgE type kappa MM on a genomic and immune repertoire level by integrating DNA- and single-cell RNA sequencing and comparative profiling against non-IgE type MM samples. We demonstrate distinct pathophysiological mechanisms as well as novel opportunities for targeting IgE type MM. Our data further provides the rationale for patient-individualized neoepitope-targeting cell therapy in high tumor mutation burden MM.


Sujet(s)
Myélome multiple , ADN , Épitopes , Humains , Myélome multiple/génétique , Phénotype , Lymphocytes T
13.
Cancers (Basel) ; 14(11)2022 May 31.
Article de Anglais | MEDLINE | ID: mdl-35681698

RÉSUMÉ

Alectinib is a standard initial treatment for patients with advanced anaplastic lymphoma kinase (ALK) rearranged non-small-cell lung cancer (NSCLC). The current study analyzed a prospective cohort of 24 consecutive alectinib-treated patients and controls in order to comprehensively characterize longitudinal erythrocyte changes under treatment with ALK inhibitors. Upon starting alectinib, all examined patients developed reticulocytosis and abnormal erythrocyte morphology with anisocytosis and a predominance of acanthocytes (64% of red blood cells on average, range 36−100%) in the peripheral blood smear within approximately 2 weeks. Changes were accompanied by a gradual reduction in Eosin-5-maleimide (EMA) binding, which became pathologic (<80% of cells) within 1−2 months in all cases, mimicking an abortive form of hereditary spherocytosis. The latter could be ruled out in 3/3 of analyzed cases by normal sequencing results for the ANK1, EPB42, SLC4A1, SPTA1, or SBTB genes. The direct Coombs test was also negative in 11/11 tested cases. Besides, anemia, increased LDH, and increased bilirubin were noted in a fraction of patients only, ranging between 42 and 68%. Furthermore, haptoglobin decreases were infrequent, occurring in approximately 1/3 of cases only, and mild, with an average value of 0.93 g/L within the normal range of 0.3−2 g/dL, suggesting that hemolysis occurred predominantly in the extravascular compartment, likely due to splenic trapping of the deformed erythrocytes. These changes showed no association with progression-free survival under alectinib or molecular features, i.e., ALK fusion variant or TP53 status of the disease, and resolved upon a switch to an alternative ALK inhibitor. Thus, alectinib induces mild, reversible erythrocyte changes in practically all treated patients, whose most sensitive signs are aberrant red cell morphology in the peripheral smear, a pathologic EMA test, and reactive reticulocytosis. Frank hemolytic anemia is rare, but mild subclinical hemolysis is very frequent and poses differential-diagnostic problems. Alectinib can be continued under the regular control of hemolysis parameters, but the risk of long-term complications, such as cholelithiasis due to increased serum bilirubin in most patients, remains unclear at present.

14.
Cell Stem Cell ; 29(5): 760-775.e10, 2022 05 05.
Article de Anglais | MEDLINE | ID: mdl-35523139

RÉSUMÉ

Hematopoietic stem and progenitor cells (HSPCs) are responsible for the production of blood and immune cells. Throughout life, HSPCs acquire oncogenic aberrations that can cause hematological cancers. Although molecular programs maintaining stem cell integrity have been identified, safety mechanisms eliminating malignant HSPCs from the stem cell pool remain poorly characterized. Here, we show that HSPCs constitutively present antigens via major histocompatibility complex class II. The presentation of immunogenic antigens, as occurring during malignant transformation, triggers bidirectional interactions between HSPCs and antigen-specific CD4+ T cells, causing stem cell proliferation, differentiation, and specific exhaustion of aberrant HSPCs. This immunosurveillance mechanism effectively eliminates transformed HSPCs from the hematopoietic system, thereby preventing leukemia onset. Together, our data reveal a bidirectional interaction between HSPCs and CD4+ T cells, demonstrating that HSPCs are not only passive receivers of immunological signals but also actively engage in adaptive immune responses to safeguard the integrity of the stem cell pool.


Sujet(s)
Présentation d'antigène , Cellules souches hématopoïétiques , Différenciation cellulaire , Lymphocytes T
15.
Nat Commun ; 12(1): 6960, 2021 11 29.
Article de Anglais | MEDLINE | ID: mdl-34845188

RÉSUMÉ

Virtually all patients with multiple myeloma become unresponsive to treatment over time. Relapsed/refractory multiple myeloma (RRMM) is accompanied by the clonal evolution of myeloma cells with heterogeneous genomic aberrations and profound changes of the bone marrow microenvironment (BME). However, the molecular mechanisms that drive drug resistance remain elusive. Here, we analyze the heterogeneous tumor cell population and its complex interaction network with the BME of 20 RRMM patients by single cell RNA-sequencing before/after treatment. Subclones with chromosome 1q-gain express a specific transcriptomic signature and frequently expand during treatment. Furthermore, RRMM cells shape an immune suppressive BME by upregulation of inflammatory cytokines and close interaction with the myeloid compartment. It is characterized by the accumulation of PD1+ γδ T-cells and tumor-associated macrophages as well as the depletion of hematopoietic progenitors. Thus, our study resolves transcriptional features of subclones in RRMM and mechanisms of microenvironmental reprogramming with implications for clinical decision-making.


Sujet(s)
Résistance aux médicaments antinéoplasiques/génétique , Régulation de l'expression des gènes tumoraux , Myélome multiple/génétique , Transcriptome , Microenvironnement tumoral/génétique , Antinéoplasiques/usage thérapeutique , Moelle osseuse/effets des médicaments et des substances chimiques , Moelle osseuse/immunologie , Moelle osseuse/anatomopathologie , Cytokines/génétique , Cytokines/immunologie , Résistance aux médicaments antinéoplasiques/immunologie , Analyse de profil d'expression de gènes , Réseaux de régulation génique , Cellules souches hématopoïétiques/immunologie , Cellules souches hématopoïétiques/anatomopathologie , Humains , Lymphocytes intra-épithéliaux/immunologie , Lymphocytes intra-épithéliaux/anatomopathologie , Myélome multiple/traitement médicamenteux , Myélome multiple/immunologie , Myélome multiple/anatomopathologie , Récepteur-1 de mort cellulaire programmée/génétique , Récepteur-1 de mort cellulaire programmée/immunologie , Récepteur lymphocytaire T antigène, gamma-delta/génétique , Récepteur lymphocytaire T antigène, gamma-delta/immunologie , Récidive , Analyse de séquence d'ARN , Transduction du signal , Analyse sur cellule unique , Microenvironnement tumoral/effets des médicaments et des substances chimiques , Microenvironnement tumoral/immunologie
16.
J Immunother Cancer ; 9(6)2021 06.
Article de Anglais | MEDLINE | ID: mdl-34112738

RÉSUMÉ

BACKGROUND: Tumor microenvironment-associated T cell senescence is a key limiting factor for durable effective cancer immunotherapy. A few studies have demonstrated the critical role of the tumor suppressor TP53-derived p53 isoforms in cellular senescence process of non-immune cells. However, their role in lymphocytes, in particular tumor-antigen (TA) specific T cells remain largely unexplored. METHODS: Human T cells from peripheral blood were retrovirally engineered to coexpress a TA-specific T cell receptor and the Δ133p53α-isoform, and characterized for their cellular phenotype, metabolic profile and effector functions. RESULTS: Phenotypic analysis of Δ133p53α-modified T cells revealed a marked reduction of the T-cell inhibitory molecules (ie, CD160 and TIGIT), a lower frequency of senescent-like CD57+ and CD160+ CD8+ T cell populations, and an increased number of less differentiated CD28+ T cells. Consistently, we demonstrated changes in the cellular metabolic program toward a quiescent T cell state. On a functional level, Δ133p53α-expressing T cells acquired a long-term proliferative capacity, showed superior cytokine secretion and enhanced tumor-specific killing in vitro and in mouse tumor model. Finally, we demonstrated the capacity of Δ133p53α to restore the antitumor response of senescent T cells isolated from multiple myeloma patients. CONCLUSION: This study uncovered a broad effect of Δ133p53α isoform in regulating T lymphocyte function. Enhancing fitness and effector functions of senescent T cells by modulation of p53 isoforms could be exploited for future translational research to improve cancer immunotherapy and immunosenescence-related diseases.


Sujet(s)
Immunothérapie/méthodes , Tumeurs/immunologie , Récepteurs aux antigènes des cellules T/métabolisme , Lymphocytes T/métabolisme , Animaux , Lignée cellulaire tumorale , Humains , Mâle , Souris , Microenvironnement tumoral
17.
Cancer Immunol Res ; 9(3): 265-278, 2021 03.
Article de Anglais | MEDLINE | ID: mdl-33563611

RÉSUMÉ

The bone marrow niche has a pivotal role in progression, survival, and drug resistance of multiple myeloma cells. Therefore, it is important to develop means for targeting the multiple myeloma bone marrow microenvironment. Myeloma-associated macrophages (MAM) in the bone marrow niche are M2 like. They provide nurturing signals to multiple myeloma cells and promote immune escape. Reprogramming M2-like macrophages toward a tumoricidal M1 phenotype represents an intriguing therapeutic strategy. This is especially interesting in view of the successful use of mAbs against multiple myeloma cells, as these therapies hold the potential to trigger macrophage-mediated phagocytosis and cytotoxicity. In this study, we observed that MAMs derived from patients treated with the immunomodulatory drug (IMiD) lenalidomide skewed phenotypically and functionally toward an M1 phenotype. Lenalidomide is known to exert its beneficial effects by modulating the CRBN-CRL4 E3 ligase to ubiquitinate and degrade the transcription factor IKAROS family zinc finger 1 (IKZF1). In M2-like MAMs, we observed enhanced IKZF1 levels that vanished through treatment with lenalidomide, yielding MAMs with a bioenergetic profile, T-cell stimulatory properties, and loss of tumor-promoting capabilities that resemble M1 cells. We also provide evidence that IMiDs interfere epigenetically, via degradation of IKZF1, with IFN regulatory factors 4 and 5, which in turn alters the balance of M1/M2 polarization. We validated our observations in vivo using the CrbnI391V mouse model that recapitulates the IMiD-triggered IKZF1 degradation. These data show a role for IKZF1 in macrophage polarization and can provide explanations for the clinical benefits observed when combining IMiDs with therapeutic antibodies.See related Spotlight on p. 254.


Sujet(s)
Facteur de transcription Ikaros/métabolisme , Lénalidomide/pharmacologie , Myélome multiple/immunologie , Microenvironnement tumoral/immunologie , Macrophages associés aux tumeurs/immunologie , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Animaux , Moelle osseuse/anatomopathologie , Lignée cellulaire tumorale , Modèles animaux de maladie humaine , Femelle , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Régulation de l'expression des gènes tumoraux/immunologie , Techniques de knock-in de gènes , Humains , Facteur de transcription Ikaros/antagonistes et inhibiteurs , Facteurs de régulation d'interféron/métabolisme , Lénalidomide/usage thérapeutique , Mâle , Souris , Souris transgéniques , Adulte d'âge moyen , Myélome multiple/traitement médicamenteux , Myélome multiple/génétique , Myélome multiple/anatomopathologie , Culture de cellules primaires , Protéolyse/effets des médicaments et des substances chimiques , Transduction du signal/effets des médicaments et des substances chimiques , Transduction du signal/génétique , Transduction du signal/immunologie , Échappement de la tumeur à la surveillance immunitaire/effets des médicaments et des substances chimiques , Échappement de la tumeur à la surveillance immunitaire/immunologie , Microenvironnement tumoral/effets des médicaments et des substances chimiques , Macrophages associés aux tumeurs/effets des médicaments et des substances chimiques , Macrophages associés aux tumeurs/métabolisme , Ubiquitination/effets des médicaments et des substances chimiques , Jeune adulte
18.
Leukemia ; 35(9): 2602-2615, 2021 09.
Article de Anglais | MEDLINE | ID: mdl-33597728

RÉSUMÉ

Elimination of suppressive T cells may enable and enhance cancer immunotherapy. Here, we demonstrate that the cell membrane protein SLAMF7 was highly expressed on immunosuppressive CD8+CD28-CD57+ Tregs in multiple myeloma (MM). SLAMF7 expression associated with T cell exhaustion surface markers and exhaustion-related transcription factor signatures. T cells from patients with a high frequency of SLAMF7+CD8+ T cells exhibited decreased immunoreactivity towards the MART-1aa26-35*A27L antigen. A monoclonal anti-SLAMF7 antibody (elotuzumab) specifically depleted SLAMF7+CD8+ T cells in vitro and in vivo via macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). Anti-SLAMF7 treatment of MM patients depleted suppressive T cells in peripheral blood. These data highlight SLAMF7 as a marker for suppressive CD8+ Treg and suggest that anti-SLAMF7 antibodies can be used to boost anti-tumoral immune responses in cancer patients.


Sujet(s)
Anticorps monoclonaux humanisés/usage thérapeutique , Déplétion lymphocytaire/méthodes , Myélome multiple/immunologie , Famille des molécules de signalisation de l'activation des lymphocytes/métabolisme , Adulte , Sujet âgé , Animaux , Antinéoplasiques/usage thérapeutique , Apoptose , Prolifération cellulaire , Femelle , Humains , Mâle , Souris , Souris de lignée NOD , Souris SCID , Adulte d'âge moyen , Myélome multiple/anatomopathologie , Myélome multiple/thérapie , Pronostic , Famille des molécules de signalisation de l'activation des lymphocytes/génétique , Cellules cancéreuses en culture , Tests d'activité antitumorale sur modèle de xénogreffe
19.
Cancers (Basel) ; 12(8)2020 Aug 18.
Article de Anglais | MEDLINE | ID: mdl-32824635

RÉSUMÉ

In order to meet the challenges in data evaluation and comparability between studies in multiple myeloma (MM) minimal residual disease (MRD) assessment, the goal of the current study was to provide a step-by-step evaluation of next-generation sequencing (NGS) and multicolor flow cytometry (MFC) data. Bone marrow (BM) sample pairs from 125 MM patients were analyzed by NGS and MFC MM MRD methods. Tumor load (TL) and limit of detection (LOD) and quantification (LOQ) were calculated. The best-fit MRD cut-off was chosen as 1 × 10-5, resulting in an overall 9.6% (n overall = 12 (NGS n = 2, MFC n = 10)) nonassessable cases. The overall concordance rate between NGS and MFC was 68.0% (n = 85); discordant results were found in 22.4% (11.2% (n = 14) of cases in each direction. Overall, 55.1% (n = 60/109) and 49.5% (n = 54/109) of patients with a serological response ≥ very good partial response (VGPR) showed BM MRD negativity by NGS and MFC, respectively. A good correlation in the TL assessed by both techniques was found (correlation coefficient = 0.8, n = 40, p < 0.001). Overall, our study shows good concordance between MM BM MRD status and TL when comparing NGS and MFC at a threshold of 10-5. However, a sufficient number of analyzed events and calculation of MRD key metrics are essential for the comparison of methods and evaluability of data at a specific MRD cut-off.

20.
Nat Cell Biol ; 22(7): 896-906, 2020 07.
Article de Anglais | MEDLINE | ID: mdl-32541878

RÉSUMÉ

Tumour heterogeneity encompasses both the malignant cells and their microenvironment. While heterogeneity between individual patients is known to affect the efficacy of cancer therapy, most personalized treatment approaches do not account for intratumour heterogeneity. We addressed this issue by studying the heterogeneity of nodal B-cell lymphomas by single-cell RNA-sequencing and transcriptome-informed flow cytometry. We identified transcriptionally distinct malignant subpopulations and compared their drug-response and genomic profiles. Malignant subpopulations from the same patient responded strikingly differently to anti-cancer drugs ex vivo, which recapitulated subpopulation-specific drug sensitivity during in vivo treatment. Infiltrating T cells represented the majority of non-malignant cells, whose gene-expression signatures were similar across all donors, whereas the frequencies of T-cell subsets varied significantly between the donors. Our data provide insights into the heterogeneity of nodal B-cell lymphomas and highlight the relevance of intratumour heterogeneity for personalized cancer therapy.


Sujet(s)
Antinéoplasiques/pharmacologie , Marqueurs biologiques tumoraux/génétique , Régulation de l'expression des gènes tumoraux , Lymphome B/anatomopathologie , Lymphocytes T/immunologie , Transcriptome/effets des médicaments et des substances chimiques , Microenvironnement tumoral/immunologie , Femelle , Analyse de profil d'expression de gènes , Humains , Lymphome B/traitement médicamenteux , Lymphome B/génétique , Lymphome B/immunologie , Mâle , Adulte d'âge moyen , Analyse de séquence d'ARN , Analyse sur cellule unique , Lymphocytes T/effets des médicaments et des substances chimiques , Lymphocytes T/métabolisme
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