Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication

An, Gang; Acharya, Chirag; Feng, Xiaoyan; Wen, Kenneth; Zhong, Mike Y; Zhang, Li; Munshi, Nikhil C.; Qiu, Lugui; Tai, Yu‐Tzu; Anderson, Kenneth C.

doi:10.1182/blood-2016-03-707547

Cited by 153 publications

(147 citation statements)

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“…IL-3 also contributes to progression of osteolytic bone disease in MM by stimulating osteoclast (OCL) formation 3,4,30–32 and inhibiting osteoblast differentiation. 31 Previous studies showed that OCL progenitor cells express IL-3 R; 30–32 consistent with these findings, we here demonstrate IL-3 R expression on OCL progenitor cells (Figure 4a).…”

Section: Resultsmentioning

confidence: 99%

“…1,2 We have shown that interactions of tumor cells with BM accessory cells (BM stromal cells, bone cells, myeloid cells, fibroblasts and immune cells) generates a conducive microenvironment for MM cells to survive, proliferate, evade cytotoxicity of drugs and escape immune responses. 1,3,4 For example, our prior studies demonstrated the functional significance of interactions between MM cells and plasmacytoid dendritic cells (pDCs) in MM pathogenesis. 5,6 Specifically, our studies showed that MM BM pDCs exhibit reduced ability to trigger T-cell proliferation compared to normal pDCs, consistent with the hallmark immune deficiency in MM.…”

Section: Introductionmentioning

confidence: 99%

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A novel agent SL-401 induces anti-myeloma activity by targeting plasmacytoid dendritic cells, osteoclastogenesis and cancer stem-like cells

et al. 2017

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Novel therapies for multiple myeloma (MM) can target mechanism(s) in the host-MM bone marrow (BM) microenvironment mediating MM progression and chemoresistance. Our studies showed increased numbers of tumor-promoting, immunosuppressive and drug-resistant plasmacytoid dendritic cells (pDCs) in the MM BM microenvironment. pDC-MM cell interactions upregulate interleukin-3 (IL-3), which stimulates both pDC survival and MM cell growth. Since IL-3 R is highly expressed on pDCs in the MM BM milieu, we here targeted pDCs using a novel IL-3 R-targeted therapeutic SL-401. In both in vitro and in vivo models of MM in its BM milieu, SL-401 decreases viability of pDCs, blocks pDC-induced MM cell growth, and synergistically enhances anti-MM activity of bortezomib and pomalidomide. Besides promoting pDC survival and MM cell growth, IL-3 also mediates progression of osteolytic bone disease in MM. Osteoclast (OCL) progenitor cells express IL-3 R, and we show that SL-401 abrogates monocyte-derived OCL formation and bone resorption. Finally, we show that SL-401 also decreases the viability of IL-3 R-expressing cancer stem-like cells in MM. Overall, our study provides the preclinical basis for clinical trials of SL-401 to block pDC-induced MM cell growth, inhibit osteoclastogenesis and target MM stem-like cell subpopulations to improve patient outcome in MM.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel agent SL-401 induces anti-myeloma activity by targeting plasmacytoid dendritic cells, osteoclastogenesis and cancer stem-like cells

et al. 2017

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“…Over the past 4 decades, we and others have developed laboratory and animal models of MM in the BM which have identified molecular and biologic mechanisms mediating tumor growth, survival, and drug resistance; and also been useful to validate novel targeted therapies (48–53). These fundamental studies both enhanced our understanding of MM pathogenesis and provided novel targets for drug discovery and development including cell surface antigens and receptors (54–56), signaling cascades (57–61), cytokines (62), and BM accessory cells (63–66). Importantly, this pioneering work validated targeting the symbiotic heterotypic interactions between the tumor cell and its microenvironment to overcome drug resistance and improve patient outcome.…”

Section: Evolution Of Therapy In MMmentioning

confidence: 99%

Progress and Paradigms in Multiple Myeloma

Anderson

2016

Clinical Cancer Research

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Remarkable progress has been achieved in multiple myeloma, and patient median survival has been extended 3-to 4-fold. Specifically, there have been 18 newly approved treatments for multiple myeloma in the past 12 years, including seven in 2015, and the treatment paradigm and patient outcome have been transformed. The definition of patients benefitting from these therapies has been broadened. Response criteria now include minimal residual disease (MRD), assessed in bone marrow by multicolor flow cytometry or sequencing, and by imaging for extramedullary disease. Initial therapy for transplant candidates is a triplet incorporating novel therapies-that is, lenalidomide, bortezomib, and dexamethasone or cyclophosphamide, bortezomib, and dexamethasone. Lenalidomide maintenance until progression can prolong progression-free and overall survival in standard-risk multiple myeloma, with incorporation of proteasome inhibitor for high-risk disease.Studies are evaluating the value of early versus late transplant and MRD as a therapeutic goal to inform therapy. In nontransplant patients, triplet therapies are also preferred, with doublet therapy reserved for frail patients, and maintenance as described above. The availability of second-generation proteasome inhibitors (carfilzomib and ixazomib), immunomodulatory drugs (pomalidomide), histone deacetylase inhibitors (panobinostat), and monoclonal antibodies (elotuzumab and daratumumab) allows for effective combination therapies of relapsed disease as well. Finally, novel therapies targeting protein degradation, restoring autologous memory anti-multiple myeloma immunity, and exploiting genetic vulnerabilities show promise to improve patient outcome even further.

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“…Osteoclasts have also been shown to contribute to an immunosuppressive microenvironment in cancer patients. Part of the immunosuppressive nature of osteoclasts is mediated by expression of checkpoint inhibitors like PD-L1, expression of T-cell metabolism regulators like indoleamine 2, 3-dioxygenase (IDO) [46] and stimulation of regulatory T cells [47], mechanisms likely to also negatively impact NK and γδT cells. Inhibition of the osteoclastogenesis is therefore proposed to create a more pro-inflammatory microenvironment in the bone marrow niche ● [46].…”

Section: 3 Potential Strategies To Simultaneously Enhance Nk and γδmentioning

confidence: 99%

NK Cells and γδT Cells for Relapse Protection after Allogeneic Hematopoietic Cell Transplantation (HCT)

2017

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Purpose of review The outcome of allogeneic stem cell transplantation (allo-HCT) is still compromised by relapse and complications. NK cells and γδT cells, effectors which both function through MHC-unrestricted mechanisms, can target transformed and infected cells without inducing Graft-versus-Host Disease (GVHD). Allo-HCT platforms based on CD34+ selection or αβ-TCR depletion result in low grades of GVHD, early immune reconstitution (IR) of NK and γδT cells and minimal usage of GVHD prophylaxis. In this review we will discuss strategies to retain and expand the quantity, diversity and functionality of these reconstituting innate cell types. Recent findings Bisphosphonates, IL-15 cytokine administration, specific antibodies, checkpoint inhibitors and (CMV based) vaccination are currently being evaluated to enhance IR. All these approaches have shown to potentially enhance both NK and γδT cell immuno-repertoires. Summary Rapidly accumulating data linking innate biology to proposed clinical immune interventions, will give unique opportunities to unravel shared pathways which determine the Graft-versus-Tumor effects of NK and γδT cells.

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Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication

Abstract: Key Points OCs play a crucial role in myeloma-induced immunosuppressive microenvironment. Therapeutic anti-CD38 mAb partially overcomes the immunosuppressive effect of OCs.

Cited by 153 publications

References 51 publications

A novel agent SL-401 induces anti-myeloma activity by targeting plasmacytoid dendritic cells, osteoclastogenesis and cancer stem-like cells

A novel agent SL-401 induces anti-myeloma activity by targeting plasmacytoid dendritic cells, osteoclastogenesis and cancer stem-like cells

Progress and Paradigms in Multiple Myeloma

NK Cells and γδT Cells for Relapse Protection after Allogeneic Hematopoietic Cell Transplantation (HCT)

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