Induction of Malignant Plasma Cell Proliferation by Eosinophils

Wong, Tina W.; Kita, Hirohito; Hanson, Curtis A.; Walters, Denise K.; Arendt, Bonnie K.; Jelinek, Diane F.

doi:10.1371/journal.pone.0070554

Cited by 30 publications

(30 citation statements)

References 38 publications

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“…Our prior work 14,20 and experiments in Figure 1 suggest that DC and MM cells themselves are important sources of CD80 and/or CD86. However, macrophages 19 and eosinophils 52 are also present in the MM microenvironment and express CD80/CD86. Nonhematopoietic stromal cells Figure 5.…”

Section: Discussionmentioning

confidence: 99%

CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma

Murray

Gavile

Nair

et al. 2014

Blood

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• CD28 delivers a pro-survival signal to MM cells via regulation of PI3K/Akt, FoxO3a, and Bim.• Blockade of CD28:CD80/ CD86 in vivo resensitizes MM cells to chemotherapy and significantly reduces tumor burden.Chemotherapeutic resistance remains a significant hurdle in the treatment of multiple myeloma (MM) and is significantly mediated by interactions between MM cells and stromal cells of the bone marrow microenvironment. Despite the importance of these interactions, the specific molecules and downstream signaling components involved remain incompletely understood. We have previously shown that the prototypic T-cell costimulatory receptor CD28, which is also expressed on MM cells, is a key mediator of MM survival and apoptotic resistance. Crosslinking CD28 by agonistic antibodies or myeloid dendritic cells (DC; these express the CD28 ligands CD80/CD86) prevents apoptosis caused by chemotherapy or serum withdrawal. We now report that CD28 pro-survival signaling is dependent upon downstream activation of phosphatidyl-inositol 3-kinase/Akt, inactivation of the transcription factor FoxO3a, and decreased expression of the pro-apoptotic molecule Bim. Conversely, blocking the CD28-CD80/CD86 interaction between MM cells and DC in vitro abrogates the DC's ability to protect MM cells against chemotherapyinduced death. Consistent with these observations, in vivo blockade of CD28-CD80/CD86 in the Vk*MYC murine myeloma model sensitizes MM cells to chemotherapy and significantly reduces tumor burden. Taken together, our findings suggest that CD28 is an important mediator of MM survival during stress and can be targeted to overcome chemotherapy resistance. (Blood. 2014;123(24): 3770-3779) IntroductionMultiple myeloma (MM), the bone marrow (BM)-resident plasma cell (PC) neoplasm, is the second most common hematologic malignancy after non-Hodgkin lymphoma.1 Although new therapies have improved survival, MM remains almost uniformly fatal and only curable in a small fraction of patients. 2,3 Initially, patients are responsive to therapy and experience remission; however, relapses result in MM cells that are progressively resistant to therapy. 3,4 Thus, understanding and overcoming resistance mechanisms may lead to development of new therapeutic approaches.Chemotherapies such as the DNA alkylator melphalan and the proteasome inhibitor bortezomib were developed because of their direct apoptotic effects on MM cells. 5,6 However, these agents, thalidomide, and thalidomide derivatives also target the BM microenvironment, pointing to the key role that stroma plays in myeloma survival.6-8 Moreover, primary MM culture in vitro requires stroma, indicating that the BM niche provides essential pro-survival signals.9-11 Thus, identifying key interactions between MM and the microenvironment is essential for understanding and overcoming therapeutic resistance mechanisms.Broadly, MM-stromal interactions fall into 2 categories. The first consists of soluble pro-survival factors induced from stromal niche cells upon MM interaction, and include int...

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Section: Discussionmentioning

confidence: 99%

CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma

Murray

Gavile

Nair

et al. 2014

Blood

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“…(20) Slides were stained either with hematoxylin and eosin (H&E) or with immunofluorescence techniques using anti-CD19 antibody (Abcam, Cambridge, MA, USA) to detect B cells and anti-MBP antibody (EMD Millipore, Billerica, MA, USA) to detect Eos. Fluorescein-conjugated goat anti-rabbit Ig (Molecular Probes, Grand Island, NY, USA) and rhodamine-conjugated goat anti-mouse Ig (Chemicon International, Billerica, MA, USA) were used as secondary antibodies.…”

Section: Methodsmentioning

confidence: 99%

“…We subsequently demonstrated that in the human PC malignancy, multiple myeloma, Eos within the tumor microenvironment can induce proliferation of the malignant cells thereby contributing to disease pathology. (20) Based on these findings, we questioned whether the proliferation-inducing effect of Eos on myeloma cells is a phenomenon that is restricted to this malignancy, or perhaps it is applicable to normal B-lineage cells as well. Indeed, via both transgenic mouse models and in vitro study of human Eos, we provide strong evidence that eosinophils do in fact impact the biology of normal B cells.…”

Section: Introductionmentioning

confidence: 99%

Eosinophils Regulate Peripheral B Cell Numbers in Both Mice and Humans

Wong

Doyle

Lee

et al. 2014

The Journal of Immunology

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The view of eosinophils (Eos) as solely effector cells involved in host parasite defense and in the pathophysiology of allergic diseases has been challenged in recent years. In fact, there is a growing realization that these cells interact with other components of innate and adaptive immunity. For example, mouse Eos were recently demonstrated to promote plasma cell retention in the bone marrow. However, it remains unknown whether Eos influence the biology of normal B lymphocytes. In this study, we specifically assessed the effect of Eos on B cell survival, proliferation, and immunoglobulin secretion. Our data first revealed that the genetic deletion of Eos from NJ1638 IL-5 transgenic hypereosinophilic mice (previously shown to display profound B cell expansion) resulted in the near abolishment of the B cell lymphocytosis. In vitro studies using human tissues demonstrated Eos’ proximity to B cell follicles and their ability to promote B cell survival, proliferation, and immunoglobulin secretion via a contact-independent mechanism(s). Additionally, this ability of Eos to enhance B cell responsiveness was observed in both T-independent and T-dependent B cell activation and appears to be independent of the Eos’ activation state. Finally, a retrospective clinical study of hypereosinophilic patients revealed for the first time a direct correlation between peripheral blood eosinophil levels and B cell numbers. Taken together, our study identifies a novel role for Eos in the regulation of humoral immunity via their impact on B cell homeostasis and proliferation upon activation.

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“…Eosinophils contribute to MM cells proliferation in a largely contact-independent manner, though not by IL-6 or APRIL, usually produced by many other kinds of BM cell types to support normal and malignant PC survival and proliferation [47]. …”

Section: Immunome: An Emerging Role In MM Microenvironmentmentioning

confidence: 99%

Immunological Dysregulation in Multiple Myeloma Microenvironment

Romano

Conticello

Cavalli

et al. 2014

BioMed Research International

110

109

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Multiple Myeloma (MM) is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC) in bone marrow (BM). Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and PC themselves. All these components are able to protect PC from cytotoxic effect of chemo- and radiotherapy. This review is focused on the role of immunome to sustain MM progression, the emerging role of myeloid derived suppressor cells, and their potential clinical implications as novel therapeutic target.

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Induction of Malignant Plasma Cell Proliferation by Eosinophils

Cited by 30 publications

References 38 publications

CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma

CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma

Eosinophils Regulate Peripheral B Cell Numbers in Both Mice and Humans

Immunological Dysregulation in Multiple Myeloma Microenvironment

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