Microenvironment Shields Myeloma From Adoptive Immunotherapy by Cell Adhesion Mediated Immune Resistance (CAM-IR),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4039-4039
Author(s):  
Sanne J de Haart ◽  
Monique C. Minnema ◽  
Tineke Aarts-Riemens ◽  
Niels Bovenschen ◽  
Henk M. Lokhorst ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
T Cell ◽  
Stromal Cells ◽  
Critical Role ◽  
Immune Resistance ◽  
Accessory Cells ◽  
Number Of Patients ◽  
Apoptosis Protein ◽  
A Cell ◽  
First Time

Abstract Abstract 4039 Cellular immunotherapy can induce long term remissions in multiple myeloma (MM) patients. Despite reported successes in a limited number of patients, the immune system fails to completely eradicate MM in the majority, proving the ability of MM cells to evade cellular immunity. The nature and mechanism of this immune escape remains not fully understood. Most studies have focused on mechanisms by which tumor cells down-regulate their antigenicity or suppress immune effector cells. Here we show a critical role for the tumor microenvironment in inducing a cell-adhesion mediated ability in MM cells to resist T cell mediated killing; a mechanism similar to cell-adhesion mediated drug resistance (CAM-DR). We used a compartment-specific bioluminescence-based viability assay, in which luciferase transduced MM cell lines were co-cultured with MM-reactive CD4+ and CD8+cytotoxic T cells (CTLs) in presence and absence of accessory cells. In these co-culture assays, we demonstrated the effective CTL-mediated lysis of MM cells. However, this lysis was significantly decreased in the presence of accessory cells, such as bone marrow stromal cells, including patient derived stromal cells, activated endothelial cells and fibroblasts. We identified that the reduction of CTL-mediated lysis was predominantly due to the induction of a cell-cell contact mediated resistance in MM cells against CTL killing, proving for the first time the existence of a cell-adhesion mediated immune resistance (CAM-IR). In support to this, blocking the adhesion of MM cells to accessory cells with an ICAM-1 antibody or with RGD peptide, which is a ligand for cell surface integrins, abrogated the resistance of MM cells against CTL-mediated lysis. Intracellular mechanisms of this immune resistance were evaluated by western blot. Adherence of MM cells to accessory cells significantly increase the expression levels of survivin in MM cells, a well known inhibitor of apoptosis protein (IAP), which blocks the CTL mediated apoptotic events via inhibiting the phosphorylation of caspase-3. Our current focus is the restoration of MM cell sensitivity to T cell mediated killing via downregulation of survivin expression. In conclusion, we report for the first time the potentially important role of microenvironment in compromising immunotherapy by the induction of CAM-IR. Our results suggest that immunotherapy may be improved by modulating the interaction of MM with its microenvironment Disclosures: No relevant conflicts of interest to declare.

Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance

2013 ◽  
Vol 19 (20) ◽  
pp. 5591-5601 ◽  
Author(s):  
Sanne J. de Haart ◽  
Niels W.C.J. van de Donk ◽  
Monique C. Minnema ◽  
Julie H. Huang ◽  
Tineke Aarts-Riemens ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Adhesion ◽  
T Cell ◽  
Cell Cytotoxicity ◽  
Immune Resistance ◽  
Accessory Cells ◽  
Cells Of The Microenvironment ◽  
T Cell Cytotoxicity

scholarly journals Role of Ly-6 in lymphocyte activation. II. Induction of T cell activation by monoclonal anti-Ly-6 antibodies.

1986 ◽  
Vol 164 (3) ◽  
pp. 709-722 ◽  
Author(s):  
T R Malek ◽  
G Ortega ◽  
C Chan ◽  
R A Kroczek ◽  
E M Shevach
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Proliferative Response ◽  
Cell Activation ◽  
Critical Role ◽  
Lymphocyte Activation ◽  
Accessory Cells ◽  
Peripheral T Cells ◽  
Activation Cascade

The Ly-6 locus controls the expression and/or encodes for alloantigenic specificities found primarily on subpopulations of murine T and B lymphocytes. We have recently identified and characterized a new rat mAb, D7, that recognizes a nonpolymorphic Ly-6 specificity. After crosslinking by anti-Ig reagents or by Fc receptor-bearing accessory cells, mAb D7 could induce IL-2 production from T cell hybridomas, and in the presence of PMA could trigger a vigorous proliferative response in resting peripheral T cells. The addition of mAb D7 to cultures of antigen- and alloantigen-, but not mitogen-stimulated T cells resulted in a marked augmentation of the proliferative response. A number of other well-characterized mAbs to Ly-6 locus products could also stimulate a T cell proliferative response after crosslinking by anti-Ig and in the presence of PMA. These results strongly suggest that Ly-6 molecules may play a critical role in the T cell activation cascade, either as receptors for an unidentified soluble or cell-associated ligand or as transducing molecules that modulate signals initiated by antigen stimulation of the T3-Ti complex.

scholarly journals Hyaluronate can function as a cell adhesion molecule and CD44 participates in hyaluronate recognition.

1990 ◽  
Vol 172 (1) ◽  
pp. 69-75 ◽  
Author(s):  
K Miyake ◽  
C B Underhill ◽  
J Lesley ◽  
P W Kincade
Keyword(s):  
Cell Adhesion ◽  
Stromal Cells ◽  
Divalent Cations ◽  
Cell Types ◽  
Lymphoid Cells ◽  
Hybridoma Cells ◽  
Antibody Treatment ◽  
A Cell ◽  
Adhesive Interactions ◽  
Potential Ligand

A cell adhesion model was previously used to select a series of monoclonal antibodies (mAbs), which were subsequently found to recognize CD44/Pgp-1. Interest in these reagents increased with the finding that they totally inhibited production of lymphoid or myeloid cells in long-term bone marrow cultures. Further investigation has now revealed that hyaluronate is a potential ligand for CD44 and that hyaluronate recognition accounts for the adhesion between B lineage hybridoma and stromal cells. The hybridoma cells adhered to hyaluronate-coated plastic wells as well as to monolayers of stromal cells. The adhesion in both cases was inhibited by treatment with hyaluronidases, and did not require divalent cations. Addition of exogenous hyaluronate also diminished binding of lymphoid cells to stromal cells. One of several mAbs to Pgp-1/CD44 was particularly effective at blocking these interactions. Since hyaluronate and Pgp-1/CD44 were present on both cell types, experiments were done to determine the cellular location of interacting molecules required for the adhesion process. Treatment of lymphoid cells with an anti-Pgp-1/CD44 antibody was more inhibitory than antibody treatment of the stromal cells. Conversely, hyaluronidase treatment of stromal cells reduced subsequent binding more than treatment of the lymphoid cells. Adhesive interactions that involve hyaluronate and CD44 could contribute to a number of cell recognition processes, including ones required for normal lympho-hemopoiesis.

scholarly journals The Na-K-ATPase α1β1 heterodimer as a cell adhesion molecule in epithelia

2012 ◽  
Vol 302 (9) ◽  
pp. C1271-C1281 ◽  
Author(s):  
Olga Vagin ◽  
Laura A. Dada ◽  
Elmira Tokhtaeva ◽  
George Sachs
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Critical Role ◽  
Cell Junction ◽  
Transepithelial Transport ◽  
Adjacent Cell ◽  
Amino Acid Region ◽  
Epithelial Junctions ◽  
A Cell

The ion gradients generated by the Na-K-ATPase play a critical role in epithelia by driving transepithelial transport of various solutes. The efficiency of this Na-K-ATPase-driven vectorial transport depends on the integrity of epithelial junctions that maintain polar distribution of membrane transporters, including the basolateral sodium pump, and restrict paracellular diffusion of solutes. The review summarizes the data showing that, in addition to pumping ions, the Na-K-ATPase located at the sites of cell-cell junction acts as a cell adhesion molecule by interacting with the Na-K-ATPase of the adjacent cell in the intercellular space accompanied by anchoring to the cytoskeleton in the cytoplasm. The review also discusses the experimental evidence on the importance of a specific amino acid region in the extracellular domain of the Na-K-ATPase β1 subunit for the Na-K-ATPase trans-dimerization and intercellular adhesion. Furthermore, a possible role of N-glycans linked to the Na-K-ATPase β1 subunit in regulation of epithelial junctions by modulating β1-β1 interactions is discussed.

scholarly journals Nanofibrillar cellulose wound dressing supports the growth and characteristics of human mesenchymal stem/stromal cells without cell adhesion coatings

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Jasmi Kiiskinen ◽  
Arto Merivaara ◽  
Tiina Hakkarainen ◽  
Minna Kääriäinen ◽  
Susanna Miettinen ◽  
...  
Keyword(s):  
Wound Healing ◽  
Cell Adhesion ◽  
Cell Viability ◽  
Cell Survival ◽  
Cell Transplantation ◽  
Stromal Cells ◽  
Wound Dressing ◽  
Nanofibrillar Cellulose ◽  
Cell Scaffold ◽  
A Cell

Abstract Background In the field of regenerative medicine, delivery of human adipose-derived mesenchymal stem/stromal cells (hASCs) has shown great promise to promote wound healing. However, a hostile environment of the injured tissue has shown considerably to limit the survival rate of the transplanted cells, and thus, to improve the cell survival and retention towards successful cell transplantation, an optimal cell scaffold is required. The objective of this study was to evaluate the potential use of wood-derived nanofibrillar cellulose (NFC) wound dressing as a cell scaffold material for hASCs in order to develop a cell transplantation method free from animal-derived components for wound treatment. Methods Patient-derived hASCs were cultured on NFC wound dressing without cell adhesion coatings. Cell characteristics, including cell viability, morphology, cytoskeletal structure, proliferation potency, and mesenchymal cell and differentiation marker expression, were analyzed using cell viability assays, electron microscopy, immunocytochemistry, and quantitative or reverse transcriptase PCR. Student’s t test and one-way ANOVA followed by a Tukey honestly significant difference post hoc test were used to determine statistical significance. Results hASCs were able to adhere to NFC dressing and maintained high cell survival without cell adhesion coatings with a cell density-dependent manner for the studied period of 2 weeks. In addition, NFC dressing did not induce any remarkable cytotoxicity towards hASCs or alter the morphology, proliferation potency, filamentous actin structure, the expression of mesenchymal vimentin and extracellular matrix (ECM) proteins collagen I and fibronectin, or the undifferentiated state of hASCs. Conclusions As a result, NFC wound dressing offers a functional cell culture platform for hASCs to be used further for in vivo wound healing studies in the future.

scholarly journals Interferon gamma plays a critical role in induced cell death of effector T cell: a possible third mechanism of self-tolerance.

1990 ◽  
Vol 172 (6) ◽  
pp. 1735-1739 ◽  
Author(s):  
Y Liu ◽  
C A Janeway
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Cyclosporin A ◽  
Interferon Gamma ◽  
Critical Role ◽  
Cell Receptor ◽  
Ifn Gamma ◽  
Accessory Cells ◽  
Self Tolerance

We have used anti-T cell monoclonal antibodies (mAbs) as mimic ligands to study the effects of T cell receptor (TCR) ligation of cloned T helper type 1 cells in the presence or absence of accessory cells. Our results demonstrate that ligation of the TCR in the absence of accessory cells rapidly induces cell death. Cell death can be prevented by addition of spleen adherent cells, leading to strong clonal expansion. Induced cell death is inhibited by cyclosporin A and by anti-interferon gamma (IFN-gamma), and is restored by adding exogenous recombinant IFN-gamma to cyclosporin A-treated cells. These results demonstrate that IFN-gamma plays a critical role in cell death induced by anti-TCR mAbs in the absence of costimulatory cells. We propose that induced cell death of active effector T cells provides a third mechanism of tolerance in addition to intrathymic deletion of developing autoreactive T cells and peripheral inactivation of mature, naive T cells.

Eradication of lymphoma by CD8 T cells following anti-CD40 monoclonal antibody therapy is critically dependent on CD27 costimulation

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4810-4815 ◽  
Author(s):  
Ruth R. French ◽  
Vadim Y. Taraban ◽  
Graham R. Crowther ◽  
Tania F. Rowley ◽  
Juliet C. Gray ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Critical Role ◽  
Antibody Therapy ◽  
Cell Immunity ◽  
Tumor Protection ◽  
Tnfr Superfamily ◽  
First Time ◽  
Dc Maturation

AbstractGrowing evidence points to the potential of agonistic anti-CD40 mAbs as adjuvants for vaccination against cancer. These appear to act by maturing dendritic cells (DCs) and allowing them to prime CD8 cytotoxic T lymphocytes (CTLs). Although it is well established that optimal T-cell priming requires costimulation via B7:CD28, recent studies emphasize the contribution of TNF receptors to this process. To understand how anti-CD40 mAbs trigger effective antitumor immunity, we investigated the role of TNFR superfamily members CD27 and 4-1BB in the generation of this immunity and showed that, although partially dependent on 4-1BB:4-1BBL engagement, it is completely reliant on CD27:CD70 interactions. Importantly, blocking CD70, and to some extent 4-1BBL, during anti-CD40 treatment prevented accumulation of tumor-reactive T cells and subsequent tumor protection. However, it did not influence changes in DC number, phenotype, nor the activity of CTLs once immunity was established. We conclude that CD27:CD70 and 4-1BB:4-1BBL interactions are needed for DC-driven accumulation of antitumor CTLs following anti-CD40 mAb treatment. Finally, in support of the critical role for CD70:CD27, we show for the first time that agonistic anti-CD27 mAbs given without a DC maturation signal completely protect tumor-bearing mice and provide a highly potent reagent for boosting antitumor T-cell immunity.

Wnt3/RhoA/ROCK Signaling Pathway Is Involved in VLA6-Dependent Adhesion-Mediated Drug Resistance of Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2518-2518
Author(s):  
Masayoshi Kobune ◽  
Yutaka Kawano ◽  
Rishu Takimoto ◽  
Takuya Matsunaga ◽  
Junji Kato ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Adhesion ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Stromal Cells ◽  
Critical Role ◽  
Rho Kinase ◽  
Myeloma Cell ◽  
Myeloma Cells

Abstract Adhesion of myeloma cells to BM stromal cells is now considered to play a critical role in chemo-resistance. However, little is known about the molecular mechanism of cell adhesion mediated drug resistance (CAM-DR) in multiple myeloma. In this study, we focused on relationship between drug resistance and expression of Wnts, the factor regulating the cell adhesion and proliferation, in myeloma cells. To gain insight into involvement of Wnt signaling in CAM-DR, we first screened the expression of Wnt family in myeloma cell lines (RPMI8226, ARH77, KMS-5 and MM1S) by reverse transcription-polymerase chain reaction analysis. Although the mRNAs of Wnt2b, Wnt7a and Wnt10b were variably expressed in some of myeloma cell lines, Wnt3 mRNA was detected in all the myeloma cells examined. KMS-5 and ARH77, which highly expressed Wnt3 protein, tightly adhered to human BM stromal cells and accumulation of β-catenin and GTP-bounded RhoA was observed in these myeloma cell lines. Conversely, RPMI8226 and MM1S, which modestly expressed Wnt3 protein, rather weakly adhered to human BM stromal cells. We then examined the relevance of Wnt3 expression to adhesive property to stromal cells and to CAM-DR of myeloma cells. KMS-5 and ARH-77 exhibited apparent CAM-DR against Doxorubicin. This CAM-DR was significantly reduced by anti-integrinβ1 antibody, anti- integrinα6 antibody and a Wnt-receptor competitor, secreted Frizzled related protein-1 and Rho kinase inhibitor (Y27632 and OH-fasudil), but not by the specific inhibitor of canonical signaling (DKK-1), indicating that Wnt-mediated CAM-DR which is dependent on integrinα6/β1 (VLA-6)-mediated attachment to stromal cells is induced by Wnt/RhoA-Rho kinase (ROCK) pathway signal. This CAM-DR for doxorubicin was also significantly reduced by Wnt3 siRNA transfer to KMS-5 and further augmented by addition of Wnt3 conditioned medium. These results indicate that Wnt3 contributes to VLA-6-mediated CAM-DR via the Wnt/RhoA/ROCK pathway of myeloma cells. Thus, the Wnt3/RhoA/ROCK signaling pathway could be a promising molecular target to overcome CAM-DR.

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