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Annals of Surgery Jul 2024To investigate the clinical relevance of common myeloid progenitor (CMP) cells in breast tumor microenvironment (TME).
Infiltration of Common Myeloid Progenitor (CMP) Cells is Associated With Less Aggressive Tumor Biology, Lower Risk of Brain Metastasis, Better Response to Immunotherapy and Higher Patient Survival in Breast Cancer.
OBJECTIVE
To investigate the clinical relevance of common myeloid progenitor (CMP) cells in breast tumor microenvironment (TME).
BACKGROUND
The role of rare cells in TME is less studied. In Silico transcriptomic analyses of real-world data enable us to detect and quantify rare cells, including CMP cells.
METHODS
Total of 5,176 breast cancer (BC) patients from SCAN-B, METABRIC, and 5 single-cell sequence cohorts were analyzed using xCell algorithm. High group was defined as more than two thirds of CMP score in each cohort.
RESULTS
CMP cells consist of 0.07-0.25% of bulk breast tumor cells, more in Estrogen Receptor-positive (ER+) compared with triple-negative (TN) subtype (0.1-0.75%, 0.18-0.33% of immune cells, respectively). CMP cells did not correlate with any of myeloid lineage nor stem cells in TME. CMP infiltration was higher in smaller tumors, with lower Nottingham grade, and in ER+/HER2- than in TNBC consistently in both SCAN-B and METABRIC cohorts. High CMP was significantly associated with lower risk of brain metastasis and with better survival, particularly in ER+/HER2- . High CMP enriched epithelial-to-mesenchymal transition and angiogenesis pathways, and less cell proliferation and DNA repair gene sets. High CMP ER+/HER2- was associated with less immune cell infiltration, and cytolytic activity (P<0.001). CMP infiltration correlated with neoadjuvant chemoimmunotherapy response for both ER+/HER2- and TNBC in the ISPY-2 cohort (AUC=0.69 and 0.74, respectively).
CONCLUSIONS
CMP in BC is inversely associated with cell-proliferation and brain metastasis, better response to immunotherapy and survival. This is the first to report the clinical relevance of CMP infiltration in BC.
PubMed: 38946549
DOI: 10.1097/SLA.0000000000006428 -
Expert Review of Anticancer Therapy Jul 2024ABBV-184, a novel survivin peptide-targeting T-cell receptor (TCR)/anti-CD3 bispecific protein, demonstrated preclinical T-cell activation and cytotoxicity toward...
BACKGROUND
ABBV-184, a novel survivin peptide-targeting T-cell receptor (TCR)/anti-CD3 bispecific protein, demonstrated preclinical T-cell activation and cytotoxicity toward HLA-A2:01-positive tumor lines. This first-in-human trial evaluated ABBV-184 monotherapy in patients with acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC).
RESEARCH DESIGN AND METHODS
This phase 1 multicenter, open-label, dose escalation trial (NCT04272203) enrolled adult patients with relapsed/refractory AML or NSCLC with an HLA-A2:01 restricted genotype. Patients received ABBV-184 at 0.07 ug/kg initially, with 2- to 3-fold dose increases. The primary objective was determining the ABBV-184 recommended phase 2 dose. Secondary objectives included safety, tolerability, pharmacokinetics, and immunogenicity assessments.
RESULTS
Fifteen patients enrolled in the dose escalation (8 AML and 7 NSCLC). ABBV-184 doses ranged from 0.07 mg/kg-0.7 µg/kg, with a half-life of approximately 13-29 hours. Transient cytokine increases were observed at all dose levels, and in patients with NSCLC, transient peripheral blood lymphocyte decreases were observed. The most frequently reported treatment-emergent adverse events (TEAEs) were anemia, diarrhea, and headache. Grade 1-2 infusion-related reaction (IRR) and cytokine release syndrome (CRS) TEAEs were reported.
CONCLUSIONS
ABBV-184 was well tolerated and demonstrated preliminary evidence of CD3 engagement with transient cytokine increases and peripheral lymphocyte decreases.
CLINICAL TRIAL REGISTRATION
NCT04272203.
PubMed: 38946484
DOI: 10.1080/14737140.2024.2373888 -
Journal of Cellular Physiology Jun 2024Skeletal muscle injury affects the quality of life in many pathologies, including volumetric muscle loss, contusion injury, and aging. We hypothesized that the...
Skeletal muscle injury affects the quality of life in many pathologies, including volumetric muscle loss, contusion injury, and aging. We hypothesized that the nicotinamide phosphoribosyltransferase (Nampt) activator P7C3 improves muscle repair following injury. In the present study, we tested the effect of P7C3 (1-anilino-3-(3,6-dibromocarbazol-9-yl) propan-2-ol) on chemically induced muscle injury. Muscle injury was induced by injecting 50 µL 1.2% barium chloride (BaCl) into the tibialis anterior (TA) muscle in C57Bl/6J wild-type male mice. Mice were then treated with either 10 mg/kg body weight of P7C3 or Vehicle intraperitoneally for 7 days and assessed for histological, biochemical, and molecular changes. In the present study, we show that the acute BaCl-induced TA muscle injury was robust and the P7C3-treated mice displayed a significant increase in the total number of myonuclei and blood vessels, and decreased serum CK activity compared with vehicle-treated mice. The specificity of P7C3 was evaluated using Nampt mice, which did not display any significant difference in muscle repair capacity among treated groups. RNA-sequencing analysis of the injured TA muscles displayed 368 and 212 genes to be exclusively expressed in P7C3 and Veh-treated mice, respectively. There was an increase in the expression of genes involved in cellular processes, inflammatory response, angiogenesis, and muscle development in P7C3 versus Veh-treated mice. Conversely, there is a decrease in muscle structure and function, myeloid cell differentiation, glutathione, and oxidation-reduction, drug metabolism, and circadian rhythm signaling pathways. Chromatin immunoprecipitation-quantitative polymerase chain reaction (qPCR) and reverse transcription-qPCR analyses identified increased Pax7, Myf5, MyoD, and Myogenin expression in P7C3-treated mice. Increased histone lysine (H3K) methylation and acetylation were observed in P7C3-treated mice, with significant upregulation in inflammatory markers. Moreover, P7C3 treatment significantly increased the myotube fusion index in the BaCl-injured human skeletal muscle in vitro. P7C3 also inhibited the lipopolysaccharide-induced inflammatory response and mitochondrial membrane potential of RAW 264.7 macrophage cells. Overall, we demonstrate that P7C3 activates muscle stem cells and enhances muscle injury repair with increased angiogenesis.
PubMed: 38946152
DOI: 10.1002/jcp.31346 -
Journal of Oleo Science 2024In this study, we evaluated the cancer cell killing activity of koji mold-derived extracts using several solvents. The koji mold lipid extract (KML) exhibited potent...
Koji Mold-derived Lipids Disrupt the Intracellular Redox State by Decreasing the GPx4 and Intracellular Glutathione Levels, Promoting Membrane Lipid Peroxidation, and Inducing Ferroptosis in HL-60 Cells.
In this study, we evaluated the cancer cell killing activity of koji mold-derived extracts using several solvents. The koji mold lipid extract (KML) exhibited potent cytotoxicity against a human leukemia cell line. Fractionation of the KML via silica gel chromatography revealed the presence of active components in fraction (Fr.) 6. Cytotoxic effects of Fr. 6 were inhibited by the ferroptosis inhibitors, ferrostatin-1 and SRS11-92, and the iron chelator, deferoxamine. Interestingly, ferroptosis inhibitors failed to prevent the KML-induced cell death. Fr. 6 decreased the expression of glutathione peroxidase 4 (GPx4) and increased the level of peroxidized plasma membrane lipids. Furthermore, Fr. 6 decreased the intracellular glutathione levels. Overall, our results suggest that Fr. 6 included in KML induces ferroptosis in HL-60 cells.
Topics: Humans; HL-60 Cells; Phospholipid Hydroperoxide Glutathione Peroxidase; Ferroptosis; Lipid Peroxidation; Glutathione; Oxidation-Reduction; Deferoxamine; Cyclohexylamines; Lipids; Phenylenediamines; Membrane Lipids; Iron Chelating Agents
PubMed: 38945927
DOI: 10.5650/jos.ess24043 -
Journal of Nutritional Science and... 2024Osteoporosis is characterized by bone loss and deterioration in bone microstructure, leading to bone fragility. It is strongly correlated with menopause in women....
Osteoporosis is characterized by bone loss and deterioration in bone microstructure, leading to bone fragility. It is strongly correlated with menopause in women. Previously, we reported that diets supplemented with a kudzu (Pueraria lobata) vine extract suppressed bone resorption in ovariectomized (OVX) mice, a postmenopausal model. The main isoflavone in kudzu is puerarin (daidzein-8-C-glycoside). Puerarin (daidzein-8-C-glycoside), which is main isoflavone of kudzu, probably contributes to the beneficial effect. However, the underlying mechanism is unclear. Therefore, the nutrikinetics of puerarin and the comparison with the suppressive effects of kudzu isoflavones on osteoclast differentiation was examined in this study. We demonstrated that orally administered puerarin was absorbed from the gut and entered the circulation in an intact form. In addition, puerarin accumulated in RAW264.7 pre-osteoclast cells in a time-dependent manner. Tartrate-resistant acid phosphatase activity was decreased by puerarin treatment in a concentration-dependent manner in RAW264.7 cells stimulated with the receptor activator of nuclear factor kappa-B ligand. Ovariectomy-induced elevated bone resorption was suppressed, and the fragile bone strength was improved by puerarin ingestion in the diet. These findings suggested that orally administered puerarin was localized in bone tissue and suppressed bone resorption and osteoclastogenesis in ovariectomized mice.
Topics: Animals; Isoflavones; Ovariectomy; Osteoclasts; Female; Mice; Femur; Pueraria; Cell Differentiation; RAW 264.7 Cells; Bone Resorption; Plant Extracts; Osteoporosis; Tartrate-Resistant Acid Phosphatase
PubMed: 38945892
DOI: 10.3177/jnsv.70.262 -
The Ocular Surface Jun 2024The lacrimal gland is essential for maintaining ocular surface health and avoiding external damage by secreting an aqueous layer of the tear film. However, a healthy...
PURPOSE
The lacrimal gland is essential for maintaining ocular surface health and avoiding external damage by secreting an aqueous layer of the tear film. However, a healthy lacrimal gland's inventory of cell types and heterogeneity remains understudied.
METHODS
Here, 10X Genome-based single-cell RNA sequencing was used to generate an unbiased classification of cellular diversity in the extraorbital lacrimal gland (ELG) of C57BL/6J mice. From 43,850 high-quality cells, we produced an atlas of cell heterogeneity and defined cell types using classic marker genes. The possible functions of these cells were analyzed through bioinformatics analysis. Additionally, the CellChat was employed for a preliminary analysis of the cell-cell communication network in the ELG.
RESULTS
Over 37 subclasses of cells were identified, including seven types of glandular epithelial cells, three types of fibroblasts, ten types of myeloid-derived immune cells, at least eleven types of lymphoid-derived immune cells, and five types of vascular-associated cell subsets. The cell-cell communication network analysis revealed that fibroblasts and immune cells play a pivotal role in the dense intercellular communication network within the mouse ELG.
CONCLUSIONS
This study provides a comprehensive transcriptome atlas and related database of the mouse ELG.
PubMed: 38945476
DOI: 10.1016/j.jtos.2024.06.005 -
Human Pathology Jun 2024The histopathological diagnosis of T-lymphoblastic leukemia/lymphoma, NOS (T-ALL), is based on morphology and positivity for CD3 and TdT. Early T-precursor lymphoblastic...
Clinicopathological differences between T-lymphoblastic leukemia/lymphoma, early T-precursor lymphoblastic leukemia/lymphoma, and mixed-phenotype acute leukemia with T lineage: an analysis of 41 adult cases.
The histopathological diagnosis of T-lymphoblastic leukemia/lymphoma, NOS (T-ALL), is based on morphology and positivity for CD3 and TdT. Early T-precursor lymphoblastic leukemia/lymphoma (ETP-ALL) and mixed-phenotype acute leukemia (MPAL), T/M, and/or B rarely occur and are usually diagnosed using flow cytometry. Using only formalin-fixed paraffin-embedded tissue raises the risk of misdiagnosis due to underestimation. Immunostaining markers for T cell (CD1a, CD4, CD5, CD8), B cell (CD19, CD10, CD22, CD79a), and stem/myeloid-related cell (CD33, CD34, CD117, MPO, lysozyme) diagnosed 25 T-ALL cases (61%), 7 MPAL (17%), 6 ETP-ALL (15%), and 3 near ETP-ALL (7%), with subsequent analysis of their clinicopathological characteristics. Patients with MPAL had significantly poorer 2-year progression-free survival (14.3% vs. 60.4%, P = 0.012) and 5-year overall survival (28.6% vs. 65.9%, P = 0.011) than did those with T-ALL, whereas ETP-ALL and near ETP-ALL did not. Of the seven patients with MPAL, three were classified as T/B, two as T/M, and two as T/M/B. Because most MPALs (6/7) share the ETP-ALL phenotype, immunohistochemistry for CD19 and MPO should be performed to avoid misdiagnosing MPAL as ETP-ALL. All three patients with TdT-negative MPAL died of the disease. Four patients with MPO-positive MPAL relapsed during the early phase (1-9 months). Five patients received the ALL regimen, but two patients received acute myeloid leukemia and lymphoma regimens, respectively. In this study, MPAL exhibited a poorer prognosis compared to T-ALL, unlike ETP-ALL. Thus, immunohistochemical classification with multiple antibody panels is useful for accurate diagnosis and treatment.
PubMed: 38945375
DOI: 10.1016/j.humpath.2024.06.016 -
International Journal of Surgery Case... Jun 2024Myeloid sarcoma (MS) is a rare extramedullary tumor composed of malignant myeloid cells that most commonly arise in patients previously diagnosed with myeloproliferative...
INTRODUCTION
Myeloid sarcoma (MS) is a rare extramedullary tumor composed of malignant myeloid cells that most commonly arise in patients previously diagnosed with myeloproliferative disease. However, they can still occur in isolation and without bone marrow disease.
CASE PRESENTATION
An 8-year-old girl who had a history of acute myeloid leukemia and was off treatment for four years presented to the clinic with a history of on and off left knee swelling and pain without any direct trauma to the knee over the last two years. Knee Magnetic resonance imaging (MRI) showed diffused joint effusion with proximal tibia focal edema. A diagnosis of juvenile rheumatoid arthritis was suspected, and the patient was started on treatment, but the problem did not resolve. Eventually, the patient underwent a repeat MRI and showed increased joint effusion with an increase in the focal edema. An open bone biopsy of the lesion was taken, and the histopathology showed sheets of primitive mononuclear cells positive for CD33 and CD117 and negative for CD34, myeloperoxidase, CD10, CD20, and CD68, indicating myeloid sarcoma.
CLINICAL DISCUSSION
Histological examination and immunohistochemistry are the most important in diagnosing myeloid sarcoma. Previously, before the introduction of chemotherapy and stem cell transplant, such cases of proximal tibia MS were treated with surgical resection of the bone. However, chemotherapy with the possibility of an allogeneic hematopoietic stem cell transplant (alloHSCT) has changed the view of survival in such cases.
CONCLUSION
Isolated proximal tibia myeloid sarcoma is a rare occurrence that can be misdiagnosed and lead to delayed treatment. Bone biopsy, Immunohistochemistry, and cytogenetic studies play a critical role in differentiating MS from other types of tumors.
PubMed: 38945014
DOI: 10.1016/j.ijscr.2024.109956 -
Journal of Extracellular Vesicles Jul 2024Haematopoiesis dysregulation with the presence of immature myeloid and erythroid immunosuppressive cells are key characteristics of the immune escape phase of tumour...
Haematopoiesis dysregulation with the presence of immature myeloid and erythroid immunosuppressive cells are key characteristics of the immune escape phase of tumour development. Here, the role of in vitro generated B16F10 tumour cell-derived extracellular vesicles (tEVs) as indirect cellular communicators, participating in tumour-induced dysregulation of haematopoiesis, was explored. The isolated tEVs displayed features of small EVs with a size range of 100-200 nm, expressed the common EV markers CD63, CD9, and Alix, and had a spherical shape with a lipid bilayer membrane. Proteomic profiling revealed significant levels of angiogenic factors, particularly vascular endothelial growth factor (VEGF), osteopontin, and tissue factor, associated with the tEVs. Systemic administration of these tEVs in syngeneic mice induced splenomegaly and disrupted haematopoiesis, leading to extramedullary haematopoiesis, expansion of splenic immature erythroid progenitors, reduced bone marrow cellularity, medullary expansion of granulocytic myeloid suppressor cells, and the development of anaemia. These effects closely mirrored those observed in tumour-bearing mice and were not seen after heat inactivating the tEVs. In vitro studies demonstrated that tEVs independently induced the expansion of bone marrow granulocytic myeloid suppressor cells and B cells while reducing the frequency of cells in the erythropoietic lineage. These effects of tEVs were significantly abrogated by the blockade of VEGF or heat inactivation. Our findings underscore the important role of tEVs in dysregulating haematopoiesis during the immune escape phase of cancer immunoediting, suggesting their potential as targets for addressing immune evasion and reinstating normal hematopoietic processes.
Topics: Animals; Extracellular Vesicles; Mice; Hematopoiesis; Melanoma, Experimental; Mice, Inbred C57BL; Vascular Endothelial Growth Factor A; Cell Line, Tumor
PubMed: 38944672
DOI: 10.1002/jev2.12471 -
Development of NR0B2 as a therapeutic target for the re-education of tumor associated myeloid cells.Cancer Letters Jun 2024Immune checkpoint blockade (ICB) has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore,...
Immune checkpoint blockade (ICB) has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. A paper co-published in this issue describes how NR0B2, a protein involved in cholesterol homeostasis, functions within myeloid immune cells to modulate the inflammasome and reduce the expansion of immune-suppressive regulatory T cells (T). Here, we develop NR0B2 as a potential therapeutic target. NR0B2 in tumors is associated with improved survival for several cancer types including breast. Importantly, NR0B2 expression is also prognostic of ICB success. Within breast tumors, NR0B2 expression is inversely associated with FOXP3, a marker of T. While a described agonist (DSHN) had some efficacy, it required high doses and long treatment times. Therefore, we designed and screened several derivatives. A methyl ester derivative (DSHN-OMe) emerged as superior in terms of (1) cellular uptake, (2) ability to regulate expected expression of genes, (3) suppression of T expansion using in vitro co-culture systems, and (4) efficacy against the growth of primary and metastatic tumors. This work identifies NR0B2 as a target to re-educate myeloid immune cells and a novel ligand with significant anti-tumor efficacy in preclinical models.
PubMed: 38944231
DOI: 10.1016/j.canlet.2024.217086