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Journal of Translational Medicine Aug 2023To gain deeper insights into the microenvironment of breast cancer, we utilized GeoMx Digital Spatial Profiling (DSP) technology to analyze transcripts from 107 regions...
To gain deeper insights into the microenvironment of breast cancer, we utilized GeoMx Digital Spatial Profiling (DSP) technology to analyze transcripts from 107 regions of interest in 65 untreated breast cancer tissue samples. Our study revealed spatial heterogeneity in the expression of marker genes in tumor cell enriched, immune cell enriched, and normal epithelial areas. We evaluated a total of 55 prognostic markers in tumor cell enriched regions and 15 in immune cell enriched regions, identifying that tumor cell enriched regions had higher levels of follicular helper T cells, resting dendritic cells, and plasma cells than immune cell enriched regions, while the levels of resting CD4 memory in T cells and regulatory (Treg) T cells were lower. Additionally, we analyzed the heterogeneity of HLA gene families, immunological checkpoints, and metabolic genes in these areas. Through univariate Cox analysis, we identified 5 prognosis-related metabolic genes. Furthermore, we conducted immunostaining experiments, including EMILIN2, SURF4, and LYPLA1, to verify our findings. Our investigation into the spatial heterogeneity of the breast cancer tumor environment has led to the discovery of specific diagnostic and prognostic markers in breast cancer.
Topics: Animals; Prognosis; Tumor Microenvironment; Mammary Neoplasms, Animal; Plasma Cells; Research Design
PubMed: 37644433
DOI: 10.1186/s12967-023-04395-x -
Cell Reports. Medicine Jul 2023Multiple myeloma (MM) is an incurable malignancy of plasma cells. To identify targets for MM immunotherapy, we develop an integrated pipeline based on mass spectrometry...
Multiple myeloma (MM) is an incurable malignancy of plasma cells. To identify targets for MM immunotherapy, we develop an integrated pipeline based on mass spectrometry analysis of seven MM cell lines and RNA sequencing (RNA-seq) from 900+ patients. Starting from 4,000+ candidates, we identify the most highly expressed cell surface proteins. We annotate candidate protein expression in many healthy tissues and validate the expression of promising targets in 30+ patient samples with relapsed/refractory MM, as well as in primary healthy hematopoietic stem cells and T cells by flow cytometry. Six candidates (ILT3, SEMA4A, CCR1, LRRC8D, FCRL3, IL12RB1) and B cell maturation antigen (BCMA) present the most favorable profile in malignant and healthy cells. We develop a bispecific T cell engager targeting ILT3 that shows potent killing effects in vitro and decreased tumor burden and prolonged mice survival in vivo, suggesting therapeutic relevance. Our study uncovers MM-associated antigens that hold great promise for immune-based therapies of MM.
Topics: Animals; Mice; Multiple Myeloma; Immunotherapy; T-Lymphocytes; Plasma Cells
PubMed: 37467717
DOI: 10.1016/j.xcrm.2023.101110 -
Immunity Feb 2024Long-lived plasma cells (PCs) secrete antibodies that can provide sustained immunity against infection. High-affinity cells are proposed to preferentially select into...
Long-lived plasma cells (PCs) secrete antibodies that can provide sustained immunity against infection. High-affinity cells are proposed to preferentially select into this compartment, potentiating the immune response. We used single-cell RNA-seq to track the germinal center (GC) development of Igh B cells, specific for the Plasmodium falciparum circumsporozoite protein (PfCSP). Following immunization with Plasmodium sporozoites, we identified 3 populations of cells in the GC light zone (LZ). One LZ population expressed a gene signature associated with the initiation of PC differentiation and readily formed PCs in vitro. The estimated affinity of these pre-PC B cells was indistinguishable from that of LZ cells that remained in the GC. This remained true when high- or low-avidity recombinant PfCSP proteins were used as immunogens. These findings suggest that the initiation of PC development occurs via an affinity-independent process.
Topics: B-Lymphocytes; Germinal Center; Plasma Cells; Cell Differentiation; Precursor Cells, B-Lymphoid
PubMed: 38228150
DOI: 10.1016/j.immuni.2023.12.010 -
Immunology Letters Aug 2023Plasma cells are the antibody secretors of the immune system. Continuous antibody secretion over years can provide long-term immune protection but could also be held...
Plasma cells are the antibody secretors of the immune system. Continuous antibody secretion over years can provide long-term immune protection but could also be held responsible for long-lasting autoimmunity in case of self-reactive plasma cells. Systemic autoimmune rheumatic diseases (ARD) affect multiple organ systems and are associated with a plethora of different autoantibodies. Two prototypic systemic ARDs are systemic lupus erythematosus (SLE) and Sjögren's disease (SjD). Both diseases are characterized by B-cell hyperactivity and the production of autoantibodies against nuclear antigens. Analogues to other immune cells, different subsets of plasma cells have been described. Plasma cell subsets are often defined dependent on their current state of maturation, that also depend on the precursor B-cell subset from which they derived. But, a universal definition of plasma cell subsets is not available so far. Furthermore, the ability for long-term survival and effector functions may differ, potentially in a disease-specific manner. Characterization of plasma cell subsets and their specificity in individual patients can help to choose a suitable targeting approach for either a broad or more selective plasma cell depletion. Targeting plasma cells in systemic ARDs is currently challenging because of side effects or varying depletion efficacies in the tissue. Recent developments, however, like antigen-specific targeting and CAR-T-cell therapy might open up major benefits for patients beyond current treatment options.
Topics: Humans; Plasma Cells; Autoimmunity; Autoantibodies; Lupus Erythematosus, Systemic; Sjogren's Syndrome; Respiratory Distress Syndrome; Autoimmune Diseases
PubMed: 37315847
DOI: 10.1016/j.imlet.2023.06.005 -
Expert Opinion on Biological Therapy 2023Autoimmune hemolytic anemia (AIHA) treatment has been revolutionized by the introduction of target therapies, mainly monoclonal antibodies (MoAbs). (Review)
Review
INTRODUCTION
Autoimmune hemolytic anemia (AIHA) treatment has been revolutionized by the introduction of target therapies, mainly monoclonal antibodies (MoAbs).
AREAS COVERED
The anti-CD20 rituximab, which targets Ab production by B-cells, induces 80% of response in warm-type AIHA (wAIHA) and 50-60% in cold agglutinin disease (CAD). Other B-cell targeting MoAbs including ianalumab, povetacicept, and obexelimab are under active study. The anti-CD38 MoAb daratumumab has been used in several reports to target long-lived plasma-cells responsible for AIHA relapse, being effective even in multi-refractory cases. Anti-complement MoAbs will soon change the treatment paradigm in CAD; the anti-C1s sutimlimab rapidly increased Hb in more than 80% of the cases. Finally, MoAbs inhibiting the neonatal Fc receptor (FcRn), such as nipocalimab, can reduce the half-life of the pathogenic autoAbs, representing a promising treatment for wAIHA.
EXPERT OPINION
MoAbs offer the potential to improve efficacy by reducing toxicity. However, there is a huge need for clinical trials exploring response duration rather than short-term efficacy. Complement inhibitors and anti-FcRns do not abrogate autoAb production and are being developed as long-term therapies. Thus, the combination of B-cell/plasma cell targeting drugs deserves to be explored. On the other hand, their rapid efficacy should be exploited for the acute AIHA phase.
Topics: Infant, Newborn; Humans; Anemia, Hemolytic, Autoimmune; Rituximab; Complement Inactivating Agents; B-Lymphocytes
PubMed: 37874225
DOI: 10.1080/14712598.2023.2274912 -
Haematologica Dec 2023Systemic light chain amyloidosis (AL) is a clonal plasma cell disorder characterized by the deposition of misfolded immunoglobulin light chains (LC) as insoluble fibrils...
Systemic light chain amyloidosis (AL) is a clonal plasma cell disorder characterized by the deposition of misfolded immunoglobulin light chains (LC) as insoluble fibrils in organs. The lack of suitable models has hindered the investigation of the disease mechanisms. Our aim was to establish AL LC-producing plasma cell lines and use them to investigate the biology of the amyloidogenic clone. We used lentiviral vectors to generate cell lines expressing LC from patients suffering from AL amyloidosis. The AL LC-producing cell lines showed a significant decrease in proliferation, cell cycle arrest, and an increase in apoptosis and autophagy as compared with the multiple myeloma LC-producing cells. According to the results of RNA sequencing the AL LC-producing lines showed higher mitochondrial oxidative stress, and decreased activity of the Myc and cholesterol pathways. The neoplastic behavior of plasma cells is altered by the constitutive expression of amyloidogenic LC causing intracellular toxicity. This observation may explain the disparity in the malignant behavior of the amyloid clone compared to the myeloma clone. These findings should enable future in vitro studies and help delineate the unique cellular pathways of AL, thus expediting the development of specific treatments for patients with this disorder.
Topics: Humans; Plasma Cells; Cell Survival; Amyloidosis; Immunoglobulin Light-chain Amyloidosis; Amyloid; Immunoglobulin Light Chains; Multiple Myeloma
PubMed: 37381778
DOI: 10.3324/haematol.2022.282484 -
Hematology/oncology Clinics of North... Apr 2024Multiple myeloma is a malignancy of bone-marrow-localized, isotype-switched plasma cells that secrete a monoclonal immunoglobulin and cause hyperCalcemia, Anemia, Renal... (Review)
Review
Multiple myeloma is a malignancy of bone-marrow-localized, isotype-switched plasma cells that secrete a monoclonal immunoglobulin and cause hyperCalcemia, Anemia, Renal failure, and lytic Bone disease. It is preceded, often for decades, by a relatively stable monoclonal gammopathy lacking these clinical and malignant features. Both conditions are characterized by the presence of types of immunoglobulin heavy gene translocations that dysregulate a cyclin D family gene on 11q13 (CCND1), 6p21 (CCND3), or 12q11 (CCND2), a maf family gene on 16q23 (MAF), 20q11 (MAFB), or 8q24 (MAFA), or NSD2/FGFR3 on 4p16, or the presence of hyperdiploidy. Subsequent loss of function of tumor suppressor genes and mutations activating MYC, RAS, NFkB, and cell cycle pathways are associated with the progression to malignant disease.
Topics: Humans; Multiple Myeloma; Translocation, Genetic; Gene Rearrangement; Mutation; Monoclonal Gammopathy of Undetermined Significance; Immunoglobulins
PubMed: 38199896
DOI: 10.1016/j.hoc.2023.12.010 -
Molecular Therapy : the Journal of the... Nov 2023Graft-versus-host disease (GVHD) is a common complication after allogeneic hematopoietic stem cell transplantation. Recent studies have reported that protein arginine...
Graft-versus-host disease (GVHD) is a common complication after allogeneic hematopoietic stem cell transplantation. Recent studies have reported that protein arginine methyltransferase 1 (PRMT1) is essential for the differentiation and proliferation of T and B cells. Therefore, it is possible that PRMT1 may play a critical role in GVHD. In this study, we observed that PRMT1 expression was upregulated in CD4 T and B cells from chronic GVHD (cGVHD) patients and mice. However, the prophylactic use of a PRMT1 inhibitor significantly prevented cGVHD in mice by reducing the percentage of T helper (Th)17 cells, germinal center B cells, and plasma cells. The PRMT1 inhibitor also controlled acute GVHD (aGVHD) in mice by decreasing the percentage of Th17 cells. Moreover, inhibiting PRMT1 also weakened Th17 cell differentiation, B cell proliferation, and antibody production in cells from cGVHD patients. Additionally, further studies revealed that PRMT1 regulated B cell proliferation and antibody secretion by methylating isocitrate dehydrogenase 2 (IDH2). We observed asymmetric di-methylation of IDH2 by PRMT1 at arginine 353 promoted IDH2 homodimerization, which enhanced IDH2 activity, further increasing B cell proliferation and antibody production. Collectively, this study provides a rationale for the application of PRMT1 inhibitors in the prevention of aGVHD and cGVHD.
Topics: Humans; Animals; Mice; Bronchiolitis Obliterans Syndrome; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; B-Lymphocytes; Plasma Cells; Methyltransferases; Protein-Arginine N-Methyltransferases; Repressor Proteins
PubMed: 37735873
DOI: 10.1016/j.ymthe.2023.09.011 -
Nature Communications Jul 2023Extrafollicular plasmablast responses (EFRs) are considered to generate antibodies of low affinity that offer little protection from infections. Paradoxically, high...
Extrafollicular plasmablast responses (EFRs) are considered to generate antibodies of low affinity that offer little protection from infections. Paradoxically, high avidity antigen-B cell receptor engagement is thought to be the main driver of B cell differentiation, whether in EFRs or slower-developing germinal centers (GCs). Here we show that influenza infection rapidly induces EFRs, generating protective antibodies via Toll-like receptor (TLR)-mediated mechanisms that are both B cell intrinsic and extrinsic. B cell-intrinsic TLR signals support antigen-stimulated B cell survival, clonal expansion, and the differentiation of B cells via induction of IRF4, the master regulator of B cell differentiation, through activation of NF-kB c-Rel. Provision of sustained TLR4 stimulation after immunization shifts the fate of virus-specific B cells towards EFRs instead of GCs, prompting rapid antibody production and improving their protective capacity over antigen/alum administration alone. Thus, inflammatory signals act as B cell fate-determinants for the rapid generation of protective antiviral extrafollicular responses.
Topics: Humans; B-Lymphocytes; Plasma Cells; Germinal Center; Toll-Like Receptors; Antigens; Inflammation; Antiviral Agents; Toll-Like Receptor 7; Toll-Like Receptor 9
PubMed: 37407556
DOI: 10.1038/s41467-023-39734-5 -
Cellular Oncology (Dordrecht) Apr 2024This study aims to identify key genes regulating tumor infiltrating plasma cells (PC) and provide new insights for innovative immunotherapy.
PURPOSE
This study aims to identify key genes regulating tumor infiltrating plasma cells (PC) and provide new insights for innovative immunotherapy.
METHODS
Key genes related to PC were identified using machine learning in lung adenocarcinoma (LUAD) patients. A prognostic model called PC scores was developed using TCGA data and validated with GEO cohorts. We assessed the molecular background, immune features, and drug sensitivity of the high PC scores group. Real-time PCR was utilized to assess the expression of hub genes in both localized LUAD patients and LUAD cell lines.
RESULTS
We constructed PC scores based on seventeen PC-related hub genes (ELOVL6, MFI2, FURIN, DOK1, ERO1LB, CLEC7A, ZNF431, KIAA1324, NUCB2, TXNDC11, ICAM3, CR2, CLIC6, CARNS1, P2RY13, KLF15, and SLC24A4). Higher age, TNM stage, and PC scores independently predicted shorter overall survival. The AUC value of PC scores for one year, three years, and five years of overall survival were 0.713, 0.716, and 0.690, separately. The nomogram model that integrated age, stage, and PC scores showed significantly higher predictive value than stage alone (P < 0.01). High PC scores group exhibited an immune suppressing microenvironment with lower B, CD8 + T, CD4 + T, and dendritic cell infiltration. Docetaxel, gefitinib, and erlotinib had lower IC50 in high PC groups (P < 0.001). After validation through the local cohort and in vitro experiments, we ultimately confirmed three key potential targets: MFI2, KLF15, and CLEC7A.
CONCLUSION
We proposed a prediction mode which can effectively identify high-risk LUAD patients and found three novel genes closely correlated with PC tumor infiltration.
Topics: Humans; Prognosis; Adenocarcinoma of Lung; Male; Female; Lung Neoplasms; Middle Aged; Plasma Cells; Treatment Outcome; Gene Expression Regulation, Neoplastic; Aged; Cell Line, Tumor; Biomarkers, Tumor; Nomograms
PubMed: 37814076
DOI: 10.1007/s13402-023-00883-w