Multiple Myeloma Impairs Bone Marrow Localization of Effector Natural Killer Cells by Altering the Chemokine Microenvironment

Ponzetta, Andrea; Benigni, Giorgia; Antonangeli, Fabrizio; Sciumé, Giuseppe; Sanseviero, Emilio; Zingoni, Alessandra; Ricciardi, Maria Rosaria; Petrucci, Maria Teresa; Santoni, Angela; Bernardini, Giovanni

doi:10.1158/0008-5472.can-15-1320

Cited by 92 publications

(96 citation statements)

References 48 publications

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“…44 Herein, we further confirmed in vivo the involvement of NK cells during tumor surveillance in melphalan-treated tumor-bearing mice by depleting NK1.1 C cells. Mice were intraperitoneally injected with anti-NK1.1 monoclonal antibody and tumor growth was shown to be higher in both PBS-and melphalan-treated NK1.1 C cell-depleted tumor-bearing mice as compared to nondepleted mice (Fig.…”

Section: Melphalan-treated MM Cells More Efficiently Trigger Nk Cell supporting

confidence: 62%

“…We chose 3 weeks after tumor injection as experimental end point to avoid the impairment of NK cell effector functions due to MM-derived alteration of NK cell trafficking as previously reported by our group. 44 Fifty micrograms of melphalan in phosphate-buffered saline (PBS), or PBS alone as sham, were intraperitoneally administered to tumor-bearing mice as illustrated in Fig. 1.…”

Section: Nkg2d and Dnam-1 Ligand Expression Is Enhanced On MM Cells Bmentioning

confidence: 99%

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Natural killer cell recognition of in vivo drug-induced senescent multiple myeloma cells

et al. 2016

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Recognition of tumor cells by the immune system is a key step in cancer eradication. Melphalan is an alkylating agent routinely used in the treatment of patients with multiple myeloma (MM), but at therapeutic doses it leads to an immunosuppressive state due to lymphopenia. Here, we used a mouse model of MM to investigate the ability of in vivo treatment with low doses of melphalan to modulate natural killer (NK) cell activity, which have been shown to play a major role in the control of MM growth. Melphalan treatment was able to enhance the surface expression of the stress-induced NKG2D ligands RAE-1 and MULT-1, and of the DNAM-1 ligand PVR (CD155) on MM cells, leading to better tumor cell recognition and killing by NK cells, as highlighted by NK cell increased degranulation triggered by melphalan-treated tumor cells. Remarkably, NK cell population was not affected by the melphalan dose used, but rather displayed activation features as indicated by CD107a and CD69 expression. Furthermore, we showed that low doses of melphalan fail to induce tumor cell apoptosis, but promote the in vivo establishment of a senescent tumor cell population, harboring high levels of the stressinduced ligands RAE-1 and PVR. Taken together our data support the concept of using chemotherapy in order to boost antitumor innate immune responses and report the possibility to induce cellular senescence of tumor cells in vivo.Abbreviations: BM, bone marrow; C 12 FDG, 5-dodecanoylaminofluorescein di-b-D-galactopyranoside; DDR, DNA damage response; DNAM-1, DNAX accessory molecule-1; IMiDs, immunomodulatory drugs; MFI, median fluorescence intensity; MM, multiple myeloma; NK cell, natural killer cell; NKG2D, natural-killer group 2 member D; PBS, phosphate-buffered saline; SA-b-Gal, senescence-associated b-galactosidase; SASP, senescence-associated secretory phenotype; X-Gal, 5-bromo-4-chloro-3-indolyl b-D-galactopyranoside

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Section: Melphalan-treated MM Cells More Efficiently Trigger Nk Cell supporting

confidence: 62%

Section: Nkg2d and Dnam-1 Ligand Expression Is Enhanced On MM Cells Bmentioning

confidence: 99%

Natural killer cell recognition of in vivo drug-induced senescent multiple myeloma cells

et al. 2016

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“…As such the role of the chemokine system in controlling the distribution of T cells within the lymphoid compartment in patients with myeloma is likely to be highly complex. Ponzetta et al have recently shown that administration of myeloma cells to immunodeficient mice leads to an increase in CXCL9 and CXCL10 within the murine bone marrow, supporting a direct role for tumour cells in the generation of inflammatory mediators [47]. In addition they also observed increased levels of CXCL10 within the bone marrow of patients with multiple myeloma and this was correlated with a decrease in the number of CXCR3+ NK cells within blood.…”

Section: Oncotarget 30389 Wwwimpactjournalscom/oncotargetmentioning

confidence: 90%

“…As such, CXCL9 [42], CXCL12 [28] and CCL3 [43] have been shown to be produced by myeloma plasma cells whereas stromal cells have been shown to produce a range of chemokines, including CCL2, CCL7, CCL8 and CCL13 from osteoclasts [44], CXCL8, CXCL11, CXCL12 and CCL2 from endothelial cells and bone marrow fibroblasts producing CXCL12 [28]. The CXCR 4/CXCR7/ (SDF) axis has been shown to be important in the recruitment of monocytic lineage cells and increased levels of CXCL12 are believed to promote the differentiation of M2 macrophages [28,30,27,32].…”

Section: Discussionmentioning

confidence: 99%

“…Increased levels of key cytokines have also been shown to progressively increase from controls to smouldering myeloma to multiple myeloma including CXCL8 (IL-8), IL-10, TNFα, IL6 and IFNγ [31] . A decrease in NK cell numbers in the bone marrow of patients with myeloma has been shown to correlate with a decrease in the chemokine CXCL12 and an upregulation of CXCR3 ligand expression [32].…”

Section: Research Papermentioning

confidence: 99%

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Neoplastic Plasma Cells Generate an Inflammatory Environment Within Bone Marrow and Markedly Alter the Distribution of T Cells Between Lymphoid Compartments

Pratt

Goodyear

Basu

et al. 2017

Clinical Lymphoma Myeloma and Leukemia

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Monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) are characterised by the accumulation of malignant plasma cells within bone marrow and lead to a range of abnormalities in the peripheral blood T cell repertoire. We investigated the level of inflammatory chemokines within the bone marrow and blood of patients with MGUS and MM and related this to the pattern of chemokine receptor expression on T cells in both compartments.The expression of a wide range of chemokine ligands for CXCR3 and CCR4 was markedly increased within the bone marrow of patients with MGUS and MM compared to healthy donors. The most marked effects were seen for CCL4 and CXCL9 which were increased by 4 and 6 fold respectively in the bone marrow of patients with myeloma. The expression of CXCR3 and CCR4, the major TH1 and TH2-associated chemokine receptors, was increased substantially on T cells within the bone marrow of patients whereas the percentage of CXCR3-expressing T cells within blood was correspondingly decreased. The presence of even small numbers of neoplastic plasma cells or associated stroma can therefore generate an inflammatory chemokine tumour microenvironment. This leads to the selective recruitment or retention of specific T cell subsets which is likely to underlie many of the features regarding the peripheral T cell repertoire in myeloma and may also contribute to the immune suppression associated with this disease. This local inflammatory reaction may represent a tumour-specific immune response or may itself play an important role in tumour progression and as such may offers a potential novel target for therapeutic intervention.

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Programmable Chemotherapy and Immunotherapy against Breast Cancer Guided by Multiplexed Fluorescence Imaging in the Second Near‐Infrared Window

et al. 2018

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to improve therapeutic effects and reduce recurrence of tumors. [3][4][5] Although there have been methodological advances, therapeutic schemes devised to challenge cancers are frequently thwarted due to the lack of correlation between the pharmacokinetics (PK) and pharmacodynamics (PD) of chemodrugs and transplanted immune cells in vivo, which results in inadequate drug/cell dosages and intervals and compromised therapeutic effects. Therefore, a visible method to objectively evaluate and therefore precisely tailor the behaviors of chemodrugs and transplanted cells in vivo to obtain synergistic therapeutic effects would be of great importance.Recently, various imaging techniques including computed tomography (CT), magnetic resonance imaging (MRI), as well as positron emission tomography (PET) and single photon emission computed tomography (SPECT) have been employed for in vivo imaging. However, it is hard to realize in situ, real-time imaging of multiple events in living bodies simultaneously due to insufficient spatial resolution, temporal resolution, as well as the safety risk. Fluorescence imaging in the second near-infrared window (NIR-II, 1000-1700 nm) is an emerging technology which offers deeper tissue penetration, higher spatial resolution, and higher temporal resolution compared with the traditional fluorescence imaging (400-900 nm), due to the reduced photon absorption and scattering as well as negligible tissue autofluorescence. In addition, fluorescence imaging provides multiplexed-channel images for its high spectral resolution. Herein, we demonstrated a novel concept of multiplexed NIR-II fluorescence imaging strategy to program the combinational therapy of tumor, in which the profiles of both chemodrugs and immune cells were simultaneously monitored by taking the advantages of NIR-II imaging technology, and therefore the administration of chemotherapy and immunotherapy could be rationally optimized to obtain the optimal therapeutic efficacy.As a proof of concept depicted in Scheme 1, a two-channel NIR-II imaging method was developed to demonstrate how the chemotherapy and immunotherapy were programed to Combined chemotherapy and immunotherapy have demonstrated great potential in cancer treatment. However, it is difficult to provide clear information of the pharmacokinetics and pharmacodynamics of chemodrugs and transplanted immune cells in vivo by traditional approaches, resulting in inadequate therapy. Here, a multiplexed intravital imaging strategy by using fluorescence in the second near-infrared window (NIR-II) is first developed to visualize the two events of chemotherapy and immunotherapy in vivo, so that a combinational administration is programed to improve the therapeutical effects against a mouse model of human breast cancer. In detail, Ag 2 Se quantum dots (QDs) (λ Em = 1350 nm) loaded with stromal-cell-derived factor-1α (SDF-1α) and chemodrug doxorubicin (DOX) are first administrated to deliver the SDF-1α and DOX to the tumor site. After their arrival, monitored by Ag 2 Se QD fluoresce...

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Multiple Myeloma Impairs Bone Marrow Localization of Effector Natural Killer Cells by Altering the Chemokine Microenvironment

Cited by 92 publications

References 48 publications

Natural killer cell recognition of in vivo drug-induced senescent multiple myeloma cells

Natural killer cell recognition of in vivo drug-induced senescent multiple myeloma cells

Neoplastic Plasma Cells Generate an Inflammatory Environment Within Bone Marrow and Markedly Alter the Distribution of T Cells Between Lymphoid Compartments

Programmable Chemotherapy and Immunotherapy against Breast Cancer Guided by Multiplexed Fluorescence Imaging in the Second Near‐Infrared Window

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