A single-cell atlas of the mouse Multiple Myeloma immune microenvironment during tumor progression
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE271306 | GEO | 2024/11/14
REPOSITORIES: GEO
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Project description:One of the hallmarks of multiple myeloma (MM) is a permissive BM microenvironment. Increasing evidence suggest that cell-to-cell communication between myeloma and immune cells via tumor cell-derived extracellular vesicles (EV) plays a key role in the pathogenesis of MM. Hence, we aimed to explore BM immune alterations induced by MM-derived EV. For this, we inoculated immunocompetent BALB/cByJ mice with a myeloma cell line - MOPC315.BM -, inducing a MM phenotype. Upon tumor establishment, characterization of the BM microenvironment revealed the expression of both activation and suppressive markers by lymphocytes, such as Granzyme b and PD-1, respectively. In addition, conditioning of the animals with MOPC315.BM-derived EV, before transplantation of the MOPC315.BM tumor cells, did not anticipate the disease phenotype. However, it induced features of suppression in the BM milieu, such as an increase in PD-1 expression by CD4+ T cells. Overall, our findings reveal the involvement of MOPC315.BM-derived EV protein content as promoters of immune niche remodeling, strengthening the importance of assessing the mechanisms by which MM may impact the immune microenvironment.
2022-07-05 | PXD032934 | Pride
Project description:Precursor states of Multiple Myeloma (MM) and its native tumor microenvironment need in-depth molecular characterization to better stratify and treat patients at risk. Using single-cell RNA sequencing of bone marrow cells from precursor stages, MGUS and smoldering myeloma (SMM), to full-blown MM alongside healthy donors, we demonstrate early immune changes during patient progression. We find NK cell abundance is frequently increased in early stages, and associated with altered chemokine receptor expression. As early as SMM, we show loss of GrK+ memory cytotoxic T-cells, and show their critical role in MM immunosurveillance in mouse models. Finally, we report MHC class II dysregulation in CD14+ monocytes, which results in T cell suppression in vitro. These results provide a comprehensive map of immune changes at play over the evolution of pre-malignant MM, which will help develop strategies for immune-based patient stratification.
2020-04-28 | GSE124310 | GEO
Project description:Although the "seed and soil" hypothesis was proposed by Stephen Paget at the end of the 19th century, where he said that tumor cells (seeds) need a propitious medium (soil) to be able to establish metastases, only recently the tumor microenvironment started to be more studied in the field of Oncology. Multiple myeloma (MM), a malignancy of plasma cells, can be considered one of the types of cancers where there is more evidence in the literature of the central role that the bone marrow (BM) microenvironment plays, contributing to proliferation, survival, migration and drug resistance of tumor cells. Despite all advances in the therapeutic arsenal for MM treatment in the last years, the disease remains incurable. Thus, studies aiming a better understanding of the pathophysiology of the disease, as well as searching for new therapeutic targets are necessary and welcome. Therefore, the present study aimed to evaluate the protein expression profiling of mononuclear cells derived from BM of MM patients in comparison with these same cell types derived from healthy individuals, in order to fill this gap in MM treatment. Proteomic analysis was performed using the mass spectrometry technique and further analyses were done using bioinformatics tools, to identify dysregulated biological pathways and/or processes in the BM microenvironment of patients with MM as a result of the disease. Among the pathways identified in this study, we can highlight an upregulation of proteins related to protein biosynthesis, especially chaperone proteins, in patients with MM. Additionally, we also found an upregulation of several proteins involved in energy metabolism, which is one of the cancer hallmarks. Finally, with regard to the downregulated proteins, we can highlight mainly those involved in different pathways of the immune response, corroborating the data that has demonstrated that the immune system of MM is impaired and, therefore, the immunotherapies that have been studied recently for the treatment of the disease are extremely necessary in the search for a control and a cure for these patients who live with the disease.
2021-04-14 | PXD019126 | Pride
Project description:Multiple Myeloma (MM) is a neoplasm of plasma cells originating in the bone marrow and is the second most common blood cancer in the United States. One challenge in understanding the pathogenesis of Multiple Myeloma (MM) and improving treatment is a lack of immunocompetent mouse models. We previously developed the IL6Myc mouse that generates plasmacytomas at 100% frequency that phenotypically resemble aggressive MM. Using comprehensive genomic analysis, we found that the RNA expression patterns between tumors were somewhat heterogenous, but nonetheless resembled MMSET (multiple myeloma SET domain), an aggressive form of human myeloma with poor prognosis. Cell lines derived from the mouse tumors expressed cell-surface markers typical of MM, but also expressed BAFF-R, which is infrequently found in human MM. The cell lines also had heterogeneous responses to chemotherapeutic drugs typically used to treat human MM. Interestingly IL6Myc tumors accumulated variants in genes like those seen in human MM, as well as recurrent Ig translocations, a common characteristic of human MM. These data indicate that the IL6Myc model is a useful model for aggressive MM that can be used to develop treatment and understand how early myc expression influences disease etiology.
2023-12-06 | GSE220827 | GEO
Project description:Direct analysis of HLA-presented antigens by mass spectrometry provides a comprehensive view on the antigenic landscape of different tissues/malignancies and enables the identification of novel, pathophysiologically relevant T-cell epitopes. Here, we present a systematic and comparative study of the HLA class I and II presented, nonmutant antigenome of multiple myeloma (MM). Quantification of HLA surface expression revealed elevated HLA molecule counts on malignant plasma cells compared with normal B cells, excluding relevant HLA downregulation in MM. Analyzing the presentation of established myeloma-associated T-cell antigens on the HLA ligandome level, we found a substantial proportion of antigens to be only infrequently presented on primary myelomas or to display suboptimal degrees of myeloma specificity. However, unsupervised analysis of our extensive HLA ligand data set delineated a panel of 58 highly specific myeloma-associated antigens (including multiple myeloma SET domain containing protein) which are characterized by frequent and exclusive presentation on myeloma samples. Functional characterization of these target antigens revealed peptide-specific, preexisting CD8+ T-cell responses exclusively in myeloma patients, which is indicative of pathophysiological relevance. Furthermore, in vitro priming experiments revealed that peptide-specific T-cell responses can be induced in response-naive myeloma patients. Together, our results serve to guide antigen selection for T-cell–based immunotherapy of MM.
2022-07-19 | PXD035324 | Pride
Project description:Multiple Myeloma (MM) is a neoplasm of plasma cells originating in the bone marrow and is the second most common blood cancer in the United States. One challenge in understanding the pathogenesis of Multiple Myeloma (MM) and improving treatment is a lack of immunocompetent mouse models. We previously developed the IL6Myc mouse that generates plasmacytomas at 100% frequency that phenotypically resemble aggressive MM. Using comprehensive genomic analysis, we found that the RNA expression patterns between tumors were somewhat heterogenous, but nonetheless resembled MMSET (multiple myeloma SET domain), an aggressive form of human myeloma with poor prognosis. Cell lines derived from the mouse tumors expressed cell-surface markers typical of MM, but also expressed BAFF-R, which is infrequently found in human MM. The cell lines also had heterogeneous responses to chemotherapeutic drugs typically used to treat human MM. Interestingly IL6Myc tumors accumulated variants in genes like those seen in human MM, as well as recurrent Ig translocations, a common characteristic of human MM. These data indicate that the IL6Myc model is a useful model for aggressive MM that can be used to develop treatment and understand how early myc expression influences disease etiology.
2023-12-06 | GSE220825 | GEO
Project description:Multiple Myeloma (MM) is a neoplasm of plasma cells originating in the bone marrow and is the second most common blood cancer in the United States. One challenge in understanding the pathogenesis of Multiple Myeloma (MM) and improving treatment is a lack of immunocompetent mouse models. We previously developed the IL6Myc mouse that generates plasmacytomas at 100% frequency that phenotypically resemble aggressive MM. Using comprehensive genomic analysis, we found that the RNA expression patterns between tumors were somewhat heterogenous, but nonetheless resembled MMSET (multiple myeloma SET domain), an aggressive form of human myeloma with poor prognosis. Cell lines derived from the mouse tumors expressed cell-surface markers typical of MM, but also expressed BAFF-R, which is infrequently found in human MM. The cell lines also had heterogeneous responses to chemotherapeutic drugs typically used to treat human MM. Interestingly IL6Myc tumors accumulated variants in genes like those seen in human MM, as well as recurrent Ig translocations, a common characteristic of human MM. These data indicate that the IL6Myc model is a useful model for aggressive MM that can be used to develop treatment and understand how early myc expression influences disease etiology.
2023-12-06 | GSE220823 | GEO
Project description:The historical lack of pre-clinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers advancing therapeutic discoveries. To circumvent this limitation, we have generated fifteen genetically diverse models that developed bone marrow tumors fulfilling MM pathogenesis. Transcriptomic analysis of tumor plasma cells revealed that MYC activation regulates time to progression. Bone marrow cell composition analysis classified myeloma tumors into immune-cold and inflamed categories, which condition immune checkpoint blockade responses in mouse multiple myeloma models.
2023-03-17 | GSE205644 | GEO
Project description:Proteasome inhibitor bortezomib (BTZ) induces apoptosis in myeloma (MM) cells, and has transformed patient outcome. Using in vitro as well as in vivo immunodeficient and immunocompetent murine MM models, we here show that BTZ also triggers immunogenic cell death (ICD) characterized by exposure of calreticulin (CALR) on dying MM cells, phagocytosis of tumor cells by dendritic cells, and induction of MM specific immunity. We identify a BTZ-triggered specific ICD-gene signature which confers improved outcome in two independent MM patient cohorts. Importantly, BTZ stimulates MM cells immunogenicity via activation of cGAS/STING pathway and production of type-I interferons; and STING agonists significantly potentiate BTZ-induced ICD. Our studies therefore delineate mechanisms whereby BTZ exerts immunotherapeutic activity, and provide the framework for clinical trials of STING agonists with BTZ to induce potent tumor-specific immunity and improve patient outcome in MM.
2021-04-12 | GSE171837 | GEO
Project description:<p>We identified germline <a href="https://www.ncbi.nlm.nih.gov/gene/?term=23028">KDM1A</a> truncating mutations in patients with multiple myeloma (MM), and loss of heterozygosity (LOH) in tumors. KDM1A mutation burden is higher in sporadic MM patients than in controls, and mRNA levels are lower in MM compared with normal plasma cells. KDM1A pharmacological inhibition in vitro promotes myeloma cell proliferation, and in mice promotes plasma cell expansion, enhanced secondary immune response to T cell dependent antigens, and upregulation of MYC oncogene transcriptional targets. Our findings provide important new insights into the role of KDM1A to suppress B cell malignancies.</p>
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