Clonal evolution after treatment pressure in multiple myeloma: heterogenous genomic aberrations and transcriptomic convergence

Leukemia, Год журнала: 2022, Номер 36(7), С. 1887 - 1897

Опубликована: Май 28, 2022

Abstract We investigated genomic and transcriptomic changes in paired tumor samples of 29 in-house multiple myeloma (MM) patients 28 from the MMRF CoMMpass study before after treatment. A change clonal composition was found 46/57 (82%) patients, single-nucleotide variants (SNVs) increased median 67 to 86. The highest increase prevalence genetic aberrations RAS genes (60% 72%), amp1q21 (18% 35%), TP53 (9% 18%). SBS-MM1 mutation signature detected both receiving high low dose melphalan. total 2589 were differentially expressed between early late (FDR < 0.05). Gene set enrichment analysis (GSEA) showed expression E2F, MYC, glycolysis pathways a decreased TNF-NFkB TGFbeta compared stage. Single sample GSEA (ssGSEA) scores revealed that these most evident end-stage disease. Increased several potentially targetable at disease stages, including cancer-testis antigens, XPO1 ABC transporters. Our demonstrates convergence supporting proliferation metabolism during progression MM.

Язык: Английский

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Integrated Multiomic Profiling Identifies the Epigenetic Regulator PRC2 as a Therapeutic Target to Counteract Leukemia Immune Escape and Relapse

Cancer Discovery, Год журнала: 2022, Номер 12(6), С. 1449 - 1461

Опубликована: Март 7, 2022

Immune escape represents a major driver of acute myeloid leukemia (AML) reemergence after allogeneic hematopoietic cell transplantation (allo-HCT), with up to 40% relapses prompted by nongenomic loss HLA class II expression in cells. By integrative analysis gene expression, DNA methylation, and chromatin accessibility paired diagnosis/relapse primary samples the respective patient-derived xenografts (PDX), we identify polycomb repressive complex 2 (PRC2) as key epigenetic this immune modality. We report that molecules is accompanied PRC2-dependent reduction accessibility. Pharmacologic inhibition PRC2 subunits rescues AML vitro vivo, consequent recovery recognition CD4+ T Our results uncover novel link between epigenetics escape, which may rapidly translate into innovative strategies cure or prevent posttransplantation relapse. Loss frequent mechanism Here main modality show its chemical can reinstate proficient graft-versus-leukemia effect, providing an rationale for personalized immunotherapies. See related commentary Köhler Zeiser, p. 1410. This article highlighted In Issue feature, 1397.

Язык: Английский

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Single-cell characterization of leukemic and non-leukemic immune repertoires in CD8+ T-cell large granular lymphocytic leukemia

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Апрель 11, 2022

Abstract T cell large granular lymphocytic leukemia (T-LGLL) is a rare lymphoproliferative disorder of mature, clonally expanded cells, where somatic-activating STAT3 mutations are common. Although T-LGLL has been described as chronic response to an antigen, the function non-leukemic immune system in this largely uncharacterized. Here, by utilizing single-cell RNA and receptor profiling (scRNA+TCRαβ-seq), we show that irrespective mutation status, clonotypes more cytotoxic exhausted than healthy reactive clonotypes. In addition, active communication clones with cells via costimulatory cell–cell interactions, monocyte-secreted proinflammatory cytokines, T-LGLL-clone-secreted IFNγ. Besides leukemic repertoire, repertoire also cytotoxic, restricted other cancers autoimmune disorders. Finally, 72% share similarities their linking repertoires together possible common target antigens. Our results provide rationale prioritize therapies entire not only clonotype.

Язык: Английский

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The Immunology of DLBCL

Cancers, Год журнала: 2023, Номер 15(3), С. 835 - 835

Опубликована: Янв. 29, 2023

Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy and the most common type of malignant lymphoid neoplasm. While some DLBCLs exhibit strong cell-autonomous survival proliferation activity, others depend on interactions with non-malignant cells for their proliferation. Recent next-generation sequencing studies have linked these molecular classification DLBCL. For example, germinal center B-cell-like DLBCL tends to show associations follicular T epigenetic regulation immune recognition molecules, whereas activated shows frequent genetic aberrations affecting class I major histocompatibility complex. Single-cell technologies also provided detailed information about cell–cell cell composition microenvironment Aging-related immunological deterioration, i.e., immunosenescence, plays important role in pathogenesis, especially Epstein-Barr virus-positive Moreover, “immune-privileged sites”—where multiple immune-modulating mechanisms exist—shows unique biological features, including down-regulation molecules immune-tolerogenic tumor microenvironment. These advances understanding immunology may contribute development novel therapies targeting systems.

Язык: Английский

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Single-cell analysis reveals altered tumor microenvironments of relapse- and remission-associated pediatric acute myeloid leukemia

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Окт. 5, 2023

Acute myeloid leukemia (AML) microenvironment exhibits cellular and molecular differences among various subtypes. Here, we utilize single-cell RNA sequencing (scRNA-seq) to analyze pediatric AML bone marrow (BM) samples from diagnosis (Dx), end of induction (EOI), relapse timepoints. Analysis Dx, EOI scRNA-seq, TARGET RNA-seq datasets reveals an blasts-associated 7-gene signature (CLEC11A, PRAME, AZU1, NREP, ARMH1, C1QBP, TRH), which validate on independent datasets. The analysis distinct clusters Dx relapse- continuous complete remission (CCR)-associated AML-blasts with differential expression genes associated survival. At relapse-associated have more exhausted T cells while CCR-associated inflammatory M1 macrophages. Post-therapy residual blasts overexpress fatty acid oxidation, tumor growth, stemness genes. Also, a post-therapy T-cell cluster downregulation MHC Class I regulatory Altogether, this study deeply characterizes provide insights into the BM landscape.

Язык: Английский

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Escape from T-cell–targeting immunotherapies in acute myeloid leukemia

Blood, Год журнала: 2023, Номер 143(26), С. 2689 - 2700

Опубликована: Июль 19, 2023

Язык: Английский

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The screening, identification, design and clinical application of tumor-specific neoantigens for TCR-T cells

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Авг. 30, 2023

Recent advances in neoantigen research have accelerated the development of tumor immunotherapies, including adoptive cell therapies (ACTs), cancer vaccines and antibody-based therapies, particularly for solid tumors. With next-generation sequencing bioinformatics technology, rapid identification prediction tumor-specific antigens (TSAs) has become possible. Compared with tumor-associated (TAAs), highly immunogenic TSAs provide new targets personalized immunotherapy can be used as prospective indicators predicting patient survival, prognosis, immune checkpoint blockade response. Here, characterization neoantigens clinical application neoantigen-based TCR-T strategies are summarized, current status, inherent challenges, translational potential these discussed.

Язык: Английский

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Combinatorial blockade for cancer immunotherapy: targeting emerging immune checkpoint receptors

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Окт. 19, 2023

The differentiation, survival, and effector function of tumor-specific CD8 + cytotoxic T cells lie at the center antitumor immunity. Due to lack proper costimulation abundant immunosuppressive mechanisms, show a persistence exhausted dysfunctional phenotypes. Multiple coinhibitory receptors, such as PD-1, CTLA-4, VISTA, TIGIT, TIM-3, LAG-3, contribute CTLs failed These receptors are collectively called immune checkpoint (ICRs). Immune inhibitors (ICIs) targeting these ICRs have become cornerstone for cancer immunotherapy they established new clinical paradigms an expanding range previously untreatable cancers. Given nonredundant yet convergent molecular pathways mediated by various ICRs, combinatorial immunotherapies being tested bring synergistic benefits patients. In this review, we summarize mechanisms several emerging including preclinical data supporting strategies improve existing ICI therapies.

Язык: Английский

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Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers

Immunity, Год журнала: 2023, Номер 56(12), С. 2816 - 2835.e13

Опубликована: Дек. 1, 2023

Cancer cells can evade natural killer (NK) cell activity, thereby limiting anti-tumor immunity. To reveal genetic determinants of susceptibility to NK we examined interacting and blood cancer using single-cell genome-scale functional genomics screens. Interaction induced distinct activation type I interferon (IFN) states in both types depending on the lineage molecular phenotype, ranging from more sensitive myeloid less B-lymphoid cancers. CRISPR screens uncovered genes regulating sensitivity resistance cell-mediated killing, including adhesion-related glycoproteins, protein fucosylation genes, transcriptional regulators, addition confirming importance antigen presentation death receptor signaling pathways. with a transcriptomic readout provided insight into underlying mechanisms, regulation IFN-γ states. Our findings highlight diversity mechanisms influencing across different cancers provide resource for cell-based therapies.

Язык: Английский

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Targeting STAT3-VISTA axis to suppress tumor aggression and burden in acute myeloid leukemia

Journal of Hematology & Oncology, Год журнала: 2023, Номер 16(1)

Опубликована: Фев. 27, 2023

Abstract The acute myeloid leukemia (AML) patients obtain limited benefits from current immune checkpoint blockades (ICBs), although immunotherapy have achieved encouraging success in numerous cancers. Here, we found that V-domain Ig suppressor of T cell activation (VISTA), a novel checkpoint, is highly expressed primary AML cells and associated with poor prognosis patients. Targeting VISTA by anti-VISTA mAb boosts cell-mediated cytotoxicity to cells. Interestingly, high expression positively hyperactive STAT3 AML. Further evidence showed functions as transcriptional regulator modulate directly binding DNA response element gene. We further develop potent selective inhibitor W1046, which significantly suppresses proliferation survival. W1046 remarkably enhances the efficacy activating via inhibition signaling down-regulation VISTA. Moreover, combination achieves significant anti-AML effect vitro vivo. Overall, our findings confirm potential target for therapy transcriptionally regulated provide promising therapeutic strategy

Язык: Английский

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