Drug-Induced Senescent Multiple Myeloma Cells Elicit NK Cell Proliferation by Direct or Exosome-Mediated IL15 <i>Trans</i>-Presentation

Borrelli, Cristiana; Ricci, Biancamaria; Vulpis, Elisabetta; Fionda, Cinzia; Ricciardi, Maria Rosaria; Petrucci, Maria Teresa; Masuelli, Laura; Peri, Agnese; Cippitelli, Marco; Zingoni, Alessandra; Santoni, Angela; Soriani, Alessandra

doi:10.1158/2326-6066.cir-17-0604

Cited by 62 publications

(60 citation statements)

References 40 publications

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“…In line with these observations, our group has recently demonstrated that melphalan stimulates the secretion of exosomes from MM cells and that these nanovesicles have the capability to trigger IFN‐γ production by NK cells with a mechanism dependent on HSP70/TLR2 interaction . The immunostimulatory property of the exosomes from drug‐induced senescent MM cells has been further proven by the finding that the exosomes express the IL‐15/IL‐15RA complex and can transpresent IL‐15, thereby promoting NK cell activation and proliferation . Collectively, these findings suggest a mechanism whereby chemotherapeutic drugs act in synergy with antitumor NK cell response by enhancing the release of nanovesicles exposing immunomodulating molecules (Fig.…”

Section: Evs As a Key Component Of Sasp Modulate Nk Cell Functionsmentioning

confidence: 54%

“…68 The immunostimulatory property of the exosomes from drug-induced senescent MM cells has been further proven by the finding that the exosomes express the IL-15/IL-15RA complex and can transpresent IL-15, thereby promoting NK cell activation and proliferation. 70 Collectively, these findings suggest a mechanism whereby chemotherapeutic drugs act in synergy with antitumor NK cell response by enhancing the release of nanovesicles exposing immunomodulating molecules (Fig. 1).…”

Section: Evs As a Key Component Of Sasp Modulate Nk Cell Functionsmentioning

confidence: 90%

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Senescent cells: Living or dying is a matter of NK cells

Antonangeli

Zingoni

Soriani

et al. 2019

Journal of Leukocyte Biology

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NK cells are lymphocytes of the innate immune system, which are able to deal promptly with stressed cells. Cellular senescence is a cell stress response leading to cell cycle arrest that plays a key role during tissue homeostasis and carcinogenesis. In this review, how senescent cells trigger an immune response and, in particular, the ability of NK cells to recognize and clear senescent cells are discussed. Special attention is given to the NK cell‐mediated clearance of senescent tumor cells. NK cells kill senescent cells through a mechanism involving perforin‐ and granzyme‐containing granule exocytosis, and produce IFN‐γ following senescent cell interaction, leading to hypothesize that NK cell‐mediated immune clearance of senescent cells not only relies on direct killing but also on cytokine production, that in turn can promote macrophage activation. These aspects, as well as the ability of the senescence‐associated secretory phenotype and senescent cell‐produced extracellular vesicles to modulate NK cell effector functions, are described.

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Section: Evs As a Key Component Of Sasp Modulate Nk Cell Functionsmentioning

confidence: 54%

Section: Evs As a Key Component Of Sasp Modulate Nk Cell Functionsmentioning

confidence: 90%

Senescent cells: Living or dying is a matter of NK cells

Antonangeli

Zingoni

Soriani

et al. 2019

Journal of Leukocyte Biology

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“…This mutual “immuno-editing” of receptor and ligand expression on the surface of NK and myeloma cells, respectively, implies a strong selective pressure of NK cells on the tumor, and suggests that strategies augmenting NK cell activity may overcome this immune evasion and eliminate MM. Finally, data that currently-used therapies (e.g., melphalan, bortezomib, lenalidomide) can augment NK cell-mediated cytotoxicity against MM ( 3 , 20 , 24 , 26 , 29 – 34 ) provide strong support for exploring combinations of NK cell-targeted therapies with these active anti-myeloma agents.…”

Section: Nk Cells and Multiple Myelomamentioning

confidence: 99%

Mechanisms of NK Cell Activation and Clinical Activity of the Therapeutic SLAMF7 Antibody, Elotuzumab in Multiple Myeloma

2018

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Multiple myeloma (MM) is a bone marrow plasma cell neoplasm and is the second most-common hematologic malignancy. Despite advances in therapy, MM remains largely incurable. Elotuzumab is a humanized IgG1 monoclonal antibody targeting SLAMF7, which is highly expressed on myeloma cells, and the antibody is approved for the treatment of relapsed and/or refractory (RR) MM in combination with lenalidomide and dexamethasone. Elotuzumab can stimulate robust antibody-dependent cellular cytotoxicity (ADCC) through engaging with FcγRIIIA (CD16) on NK cells and antibody-dependent cellular phagocytosis (ADCP) by macrophages. Interestingly, SLAMF7 is also expressed on cytolytic NK cells, which also express the requisite adaptor protein, EAT-2, to mediate activation signaling. Accumulating evidence indicates that antibody crosslinking of SLAMF7 on human and mouse NK cells can stimulate EAT-2-dependent activation of PLCγ, ERK, and intracellular calcium mobilization. The binding of SLAMF7 by elotuzumab can directly induce signal transduction in human NK cells, including co-stimulation of the calcium signaling triggered through other surface receptors, such as NKp46 and NKG2D. In RRMM patients, elotuzumab monotherapy did not produce objective responses, but did enhance the activity of approved standard of care therapies, including lenalidomide or bortezomib, which are known to enhance anti-tumor responses by NK cells. Taken together, these preclinical results and accumulating experience in the clinic provide compelling evidence that the mechanism of action of elotuzumab in MM patients involves the activation of NK cells through both CD16-mediated ADCC and direct co-stimulation via engagement with SLAMF7, as well as promoting ADCP by macrophages. We review the current understanding of how elotuzumab utilizes multiple mechanisms to facilitate immune-mediated attack of myeloma cells, as well as outline goals for future research.

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“…Chemotherapy induces SASP containing IL15RA and IL-15 in MM and increased expression of IL-15/IL15RA on the membrane of senescent myeloma cells. These events allow the functional trans-presentation of IL-15 to neighboring NK cells leading to NK cell recognition and cytotoxicity [ 194 ]. Moreover, additional NK mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) are activated after chemotherapy to eliminate senescent breast cancer cells, where doxorubicin enhances senescence through SASP secretion leading to a perforin-dependent increase in ADCC by NK cells [ 195 ].…”

Section: Clinical Relevance Of Senescence In Immunotherapy: a Balamentioning

confidence: 99%

Senescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword

Battram

Bachiller

Martín-Antonio

2020

IJMS

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Cellular senescence was first described as a physiological tumor cell suppressor mechanism that leads to cell growth arrest with production of the senescence-associated secretory phenotype known as SASP. The main role of SASP in physiological conditions is to attract immune cells to clear senescent cells avoiding tumor development. However, senescence can be damage-associated and, depending on the nature of these stimuli, additional types of senescence have been described. In the context of cancer, damage-associated senescence has been described as a consequence of chemotherapy treatments that were initially thought of as a tumor suppressor mechanism. However, in certain contexts, senescence after chemotherapy can promote cancer progression, especially when immune cells become senescent and cannot clear senescent tumor cells. Moreover, aging itself leads to continuous inflammaging and immunosenescence which are responsible for rewiring immune cells to become defective in their functionality. Here, we define different types of senescence, pathways that activate them, and functions of SASP in these events. Additionally, we describe the role of senescence in cancer and its treatments, including how aging and chemotherapy contribute to senescence in tumor cells, before focusing on immune cell senescence and its role in cancer. Finally, we discuss potential therapeutic interventions to reverse cell senescence.

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Drug-Induced Senescent Multiple Myeloma Cells Elicit NK Cell Proliferation by Direct or Exosome-Mediated IL15 Trans-Presentation

Cited by 62 publications

References 40 publications

Senescent cells: Living or dying is a matter of NK cells

Senescent cells: Living or dying is a matter of NK cells

Mechanisms of NK Cell Activation and Clinical Activity of the Therapeutic SLAMF7 Antibody, Elotuzumab in Multiple Myeloma

Senescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword

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