scholarly journals The bone marrow stromal compartment in multiple myeloma patients retains capability for osteogenic differentiationin vitro: defining the stromal defect in myeloma

2014 ◽  
Vol 167 (2) ◽  
pp. 194-206 ◽  
Author(s):  
Deepika Kassen ◽  
Sally Moore ◽  
Laura Percy ◽  
Gaelle Herledan ◽  
Danton Bounds ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stromal Compartment ◽  
Differentiationin Vitro

Role Of Decorin In Multiple Myeloma (MM) Bone Marrow Microenvironment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1851-1851
Author(s):  
Neeharika Nemani ◽  
Loredana Santo ◽  
Homare Eda ◽  
Diana Cirstea ◽  
Yuko Mishima ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Viability ◽  
Healthy Volunteers ◽  
Mrna Expression ◽  
Stromal Cells ◽  
Research Funding ◽  
Stromal Compartment ◽  
Trap Staining ◽  
And Function

Abstract Decorin is a small leucine rich proteoglycan found in the extracellular matrix of various connective tissues with potential effective tumor suppressor properties. Recently, it has been shown that decorin decreases in multiple myeloma (MM) patients compared to healthy volunteers, and also in patients with osteolytic bone lesions than non-osteolytic lesions. By using a cytokine array analysis we showed that decorin is down regulated in patients withdrawn from aminobisphosphanates for six months. These results led us to focus on decorin and its role in the bone marrow micro environment. We looked at the expression of decorin in MM cell lines. The mRNA expression of decorin in MM cells (OPM1, OPM2, RPMI, INA6, U266, KMS18 and KMS20) was not detectable when compared to MG63, an osteosarcoma cell line that constitutively produces decorin. Consistent with the mRNA expression, decorin protein secretion was also very low in the MM cell lines as demonstrated by ELISA. A 48 hour MTT assay on OPM1, OPM2, RPMI, MM1.S and CD138+ patient myeloma cells with increasing concentrations (0, 5, 10, 20 and 40μg/ml) of exogenous decorin did not show a significant decrease in cell viability. These results indicate that decorin is not produced by MM cells and does not have a direct effect on MM cell viability. Having looked at decorin in the tumor, we then observed its expression in the stromal compartment. We investigated decorin mRNA and protein expression in bone marrow stromal cells (BMSC), osteoclasts (OC) and osteoblats (OB) differentiated from MM patients. BMSC and OB, differentiated for 4 and 7 days, showed a significantly higher expression of decorin compared to the OC. Decorin secretion was more pronounced by differentiating OB than BMSCs. Consistent with previously reported data, we also found that decorin protein levels were higher in BMSCs and OB differentiated for 4 and 7 days from healthy volunteers than MM patients. Moreover, addition of exogenous decorin (at 5 and 10 μg/ml) to OB increased OB differentiation as seen by increased mRNA expression for markers of OB differentiation (alkaline phosphatase and RUNX2) suggesting that decorin plays a role in OB differentiation. Given the significance of the interaction between the MM tumor and its micro-environment we next evaluated the effect of decorin in the stroma when co-cultured with MM cells. Decorin mRNA levels were down regulated when OPM2 cells were co-cultured without direct cell contact with BMSC and OB differentiated for 4 and 7 days suggesting that MM cells decreased decorin and the effect is probably cytokine mediated. Having studied the effect of decorin on OB in the stromal compartment, we then focused on the OCs. When exogenous decorin was added at 5 and 10mg/ml to peripheral blood mononuclear cells from MM patients in OC differentiation media for 7, 14 and 21 days of differentiation, there was a significant decrease in OC number as observed by TRAP staining (80% decrease in OC number in 5mg/ml and 95% decrease in 10mg/ml compared to control). Decorin at the same concentrations greatly decreased the area of pits as compared to the control (43% decrease in area of pit in 5mg/ml and 67% decrease in 10mg/ml compared to control) suggesting that exogenous decorin inhibited OC differentiation and function. TRAP staining and MTT assays on 14 day mature OCs with decorin treated for 48 hours after maturation, did not show a decrease in cell number and viability of OC indicating that decorin does not affect mature OCs. In conclusion, our data suggests that decorin secreted by stromal cells and in particular differentiating OBs, does not directly affect the viability of MM cells. It inhibits OC differentiation and function and promotes OB differentiation. Importantly, decorin levels decreased significantly in the BMSC and OB when co-cultured with MM cells. We speculate that this decrease is a result of decreased OB differentiation by MM cells. Since, all the above lines of evidence point to decorin modulating the myeloma microenvironment with potential indirect anti-tumor effects without acting as a direct antagonist to the tumor, ongoing studies that understand mechanisms to stimulate decorin secretion can prove to be useful with respect to MM microenvironment interactions. Disclosures: Raje: Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Amgen: Consultancy; Acetylon: Consultancy, Research Funding; Eli Lilly: Research Funding.

Deregulation of the bone marrow stromal compartment occurs early in multiple myeloma and precedes osteolytic bone disease

Bone ◽  
2011 ◽  
Vol 48 ◽  
pp. S253-S254
Author(s):  
D. Kassen ◽  
N. Rabin ◽  
D. Lath ◽  
P. Croucher ◽  
K. Yong
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Disease ◽  
Stromal Compartment ◽  
Osteolytic Bone Disease

Bone disease as the first manifestation of systemic AL-amyloidosis

2020 ◽  
Vol 92 (7) ◽  
pp. 85-89
Author(s):  
L. P. Mendeleeva ◽  
I. G. Rekhtina ◽  
A. M. Kovrigina ◽  
I. E. Kostina ◽  
V. A. Khyshova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Disease ◽  
Plasma Cells ◽  
Interventricular Septum ◽  
Bone Destruction ◽  
Amyloid Deposition ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
Linear Type

Our case demonstrates severe bone disease in primary AL-amyloidosis without concomitant multiple myeloma. A 30-year-old man had spontaneous vertebral fracture Th8. A computed tomography scan suggested multiple foci of lesions in all the bones. In bone marrow and resected rib werent detected any tumor cells. After 15 years from the beginning of the disease, nephrotic syndrome developed. Based on the kidney biopsy, AL-amyloidosis was confirmed. Amyloid was also detected in the bowel and bone marrow. On the indirect signs (thickening of the interventricular septum 16 mm and increased NT-proBNP 2200 pg/ml), a cardial involvement was confirmed. In the bone marrow (from three sites) was found 2.85% clonal plasma cells with immunophenotype СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. FISH method revealed polysomy 5,9,15 in 3% of the nuclei. Serum free light chain Kappa 575 mg/l (/44.9) was detected. Multiple foci of destruction with increased metabolic activity (SUVmax 3.6) were visualized on PET-CT, and an surgical intervention biopsy was performed from two foci. The number of plasma cells from the destruction foci was 2.5%, and massive amyloid deposition was detected. On CT scan foci of lesions differed from bone lesions at multiple myeloma. Bone fragments of point and linear type (button sequestration) were visualized in most of the destruction foci. The content of the lesion was low density. There was no extraossal spread from large zones of destruction. There was also spontaneous scarring of the some lesions (without therapy). Thus, the diagnosis of multiple myeloma was excluded on the basis based on x-ray signs, of the duration of osteodestructive syndrome (15 years), the absence of plasma infiltration in the bone marrow, including from foci of bone destruction by open biopsy. This observation proves the possibility of damage to the skeleton due to amyloid deposition and justifies the need to include AL-amyloidosis in the spectrum of differential diagnosis of diseases that occur with osteodestructive syndrome.

154 Marrow-infiltrating lymphocytes (MILs): A novel adoptive immunotherapy for hematological and solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A168-A168
Author(s):  
Eric Lutz ◽  
Lakshmi Rudraraju ◽  
Elizabeth DeOliveira ◽  
Amanda Seiz ◽  
Monil Shah ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Cancer ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
Memory T Cells ◽  
Small Cell ◽  
Small Cell Lung ◽  
Blood Samples ◽  
Infiltrating Lymphocytes

BackgroundMarrow infiltrating lymphocytes (MILsTM) are the product of activating and expanding bone marrow T cells.1 The bone marrow is a specialized niche in the immune system enriched for antigen-experienced, memory T cells. In patients with multiple myeloma and other hematological malignancies that relapse post-transplant, MILs have been shown to contain tumor antigen-specific T cells and adoptive cell therapy (ACT) using MILs has demonstrated antitumor activity.2 3 The bone marrow has been shown to harbor tumor-antigen specific T cells in patients with melanoma,4 5 glioblastoma,6 breast,7 non-small-cell lung8 and pancreatic cancers.9 Here, we sought to determine if tumor-specific MILs could be expanded from the bone marrow of patients with a range of different solid tumors.MethodsBone marrow and blood samples were collected from patients with advanced and metastatic cancers. To date, samples have been collected from a minimum of four patients with non-small cell lung cancer (NSCLC), prostate cancer, head and neck cancer, glioblastoma, and breast cancer. Samples from patients with multiple myeloma were used as a reference control. Utilizing a 10-day proprietary process, MILs and peripheral blood lymphocytes (PBLs) were activated and expanded from patient bone marrow and blood samples, respectively. T cell lineage-specific markers (CD3, CD4 and CD8) were characterized by flow cytometry pre- and post-expansion.Tumor-specific T cells were quantitated in expanded MILs and PBLs using a previously described cytokine-secretion assay [2]. Briefly, autologous antigen-presenting cells (APCs) were pulsed with lysates from allogeneic cancer cell lines and co-cultured with activated MILs or PBLs. APCs pulsed with irrelevant mis-matched cancer cell line lysates or media alone were used as negative controls. Tumor-specific T cells were defined as the IFNgamma-producing population by flow cytometry.ResultsMILs were successfully expanded from all patient bone marrow samples tested, regardless of tumor type. Cytokine-producing tumor-specific CD4+ and CD8+ T cells were detected in each of the expanded MILs. In contrast, tumor-specific T cells were not detected in any of the matched activated and expanded PBLs.ConclusionsMILs have been successfully grown for all solid tumor types evaluated, including NSCLC, prostate, head and neck, glioblastoma and breast cancer. Clinical studies have been completed in patients with multiple myeloma and other hematological cancers. 2 3 A phase IIa trial to evaluate MILs in combination with a checkpoint inhibitor is underway in patients with anti-PD1/PDL1-refractory NSCLC (ClinicalTrials.gov Identifier: NCT04069936). The preclinical data presented herein demonstrate that expanding MILs is feasible. MILs-based therapies hold therapeutic promise across a wide range of tumor indications.Ethics ApprovalThis study was approved by each participating instituion’s IRB.ReferencesBorrello I and Noonan KA. Marrow-Infiltrating Lymphocytes - Role in Biology and Cancer Therapy. Front Immunol 2016 March 30; 7(112)Noonan KA, Huff CA, Davis J, et al. Adoptive transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma. Sci. Transl. Med 2015;7:288ra78.Biavati L, Noonan K, Luznik L, Borrello I. Activated allogeneic donor-derived marrow-infiltrating lymphocytes display measurable in vitro antitumor activity. J Immunother 2019 Apr;42(3):73–80.Müller-Berghaus J, Ehlert K, Ugurel S, et al. Melanoma-reactive T cells in the bone marrow of melanoma patients: association with disease stage and disease duration. Cancer Res 2006;66(12):5997–6001.Letsch A, Keilholz U, Assfalg G, et al., Bone marrow contains melanoma-reactive CD8+ effector T Cells and, compared with peripheral blood, enriched numbers of melanoma-reactive CD8+ memory T cells. Cancer Res 2003 Sep 1;63(17):5582–5586.Chongsathidkiet P, Jackson C, Koyama S, et al., Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nature Medicine 2018 Aug 13; 24:1459–1468.Feuerer M, Rocha M, Bai L, et al. Enrichment of memory T cells and other profound immunological changes in the bone marrow from untreated breast cancer patients. Int J Cancer 2001; 92(1):96–105.Safi S, Yamauchi Y, Stamova S, et al. Bone marrow expands the repertoire of functional T cells targeting tumor-associated antigens in patients with resectable non-small-cell lung cancer. Oncoimmunology 2019;8(12):e1671762.Schmitz-Winnenthal FH, Volk C, Z’Graggen K, et al. High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients. Cancer Res 2005;65(21):10079–87.

scholarly journals PD-L1/PD-1 Axis in Multiple Myeloma Microenvironment and a Possible Link with CD38-Mediated Immune-Suppression

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 164
Author(s):  
Federica Costa ◽  
Valentina Marchica ◽  
Paola Storti ◽  
Fabio Malavasi ◽  
Nicola Giuliani
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Survival ◽  
Immune Suppression ◽  
Metabolic Pathways ◽  
Therapeutic Strategy ◽  
Myeloma Cell ◽  
Immune Microenvironment ◽  
Potential Use

The emerging role of the PD-1/PD-L1 axis in MM immune-microenvironment has been highlighted by several studies. However, discordant data have been reported on PD-1/PD-L1 distribution within the bone marrow (BM) microenvironment of patients with monoclonal gammopathies. In addition, the efficacy of PD-1/PD-L1 blockade as a therapeutic strategy to reverse myeloma immune suppression and inhibit myeloma cell survival still remains unknown. Recent data suggest that, among the potential mechanisms behind the lack of responsiveness or resistance to anti-PD-L1/PD-1 antibodies, the CD38 metabolic pathways involving the immune-suppressive factor, adenosine, could play an important role. This review summarizes the available data on PD-1/PD-L1 expression in patients with MM, reporting the main mechanisms of regulation of PD-1/PD-L1 axis. The possible link between the CD38 and PD-1/PD-L1 pathways is also reported, highlighting the rationale for the potential use of a combined therapeutic approach with CD38 blocking agents and anti-PD-1/PD-L1 antibodies in order to improve their anti-tumoral effect in MM patients.

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