Nutlin-3a Enhances Natural Killer Cell–Mediated Killing of Neuroblastoma by Restoring p53-Dependent Expression of Ligands for NKG2D and DNAM-1 Receptors

Treatment of metastatic pediatric solid tumors remain a significant challenge, particularly in relapsed and refractory settings. Standard treatment has included surgical resection, radiation, chemotherapy, and, in the case of neuroblastoma, immunotherapy. Despite such intensive therapy, cancer recurrence is common, and most tumors become refractory to prior therapy, leaving patients with few conventional treatment options. Natural killer (NK) cells are non-major histocompatibility complex (MHC)-restricted lymphocytes that boast several complex killing mechanisms but at an added advantage of not causing graft-versus-host disease, making use of allogeneic NK cells a potential therapeutic option. On top of their killing capacity, NK cells also produce several cytokines and growth factors that act as key regulators of the adaptive immune system, positioning themselves as ideal effector cells for stimulating heavily pretreated immune systems. Despite this promise, clinical efficacy of adoptive NK cell therapy to date has been inconsistent, prompting a detailed understanding of the biological pathways within NK cells that can be leveraged to develop “next generation” NK cell therapies. Here, we review advances in current approaches to optimizing the NK cell antitumor response including combination with other immunotherapies, cytokines, checkpoint inhibition, and engineering NK cells with chimeric antigen receptors (CARs) for the treatment of pediatric solid tumors.

Section: Nk Cell Activating and Inhibitory Receptorsmentioning

confidence: 99%

Approaches to Enhance Natural Killer Cell-Based Immunotherapy for Pediatric Solid Tumors

Quamine

Olsen

Cho

et al. 2021

“…The cross-talk between NK cells and solid tumor cells has also been assessed using spheroids of neuroblastoma, ovarian, cervical and breast carcinomas [ 121 , 123 , 163 , 164 , 165 ]. Neuroblastoma spheroids have been used to assess NK-cell mediated cytotoxicity upon treatment with nutlin-3a, a small molecule that antagonizes the inhibitory effect of MDM2 on p53.…”

Section: Tumor Cell Spheroids As a 3d Model To Study Tumor Cell Biology And Tumor-natural Killer Cross-talkmentioning

confidence: 99%

“…Neuroblastoma spheroids have been used to assess NK-cell mediated cytotoxicity upon treatment with nutlin-3a, a small molecule that antagonizes the inhibitory effect of MDM2 on p53. The reactivation of p53 triggered the upregulation of DNAM1 ligands on neuroblastoma cells activating NK cell recognition and killing [ 165 ]. NK cells cultured with spheroids of ovarian cancer cells (IGROV1, SKOV3, OVCAR3) can downregulate the expression of DNAM1, the same happens co-culturing ovarian cancer specimens with NK cells [ 121 ].…”

Section: Tumor Cell Spheroids As a 3d Model To Study Tumor Cell Biology And Tumor-natural Killer Cross-talkmentioning

confidence: 99%

“…Another challenge in a 3D culture models is the quantitative analysis of the cytotoxicity of NK cells in tumor cells. This can be achieved evaluating different parameters in tumor cells: caspase activation, increment/reduction of fluorescent probes (passive markers, active substrates, or reporter constructs), and residual living cells quantification [ 119 , 121 , 123 , 128 , 160 , 163 , 165 , 166 , 168 , 170 , 171 , 178 , 179 ]. The quantitative analysis of killing has been assessed mainly by image analysis [ 119 , 126 , 128 , 212 , 214 , 215 ].…”

Section: Tumor Cell Organoids: a More Reliable 3d Model To Study Tumor Cell Biology And Tumor-nk Cells Interactions?mentioning

confidence: 99%

See 1 more Smart Citation

Three-Dimensional Culture Models to Study Innate Anti-Tumor Immune Response: Advantages and Disadvantages

Poggi

Villa

Fernadez

et al. 2021

Several approaches have shown that the immune response against tumors strongly affects patients’ clinical outcome. Thus, the study of anti-tumor immunity is critical to understand and potentiate the mechanisms underlying the elimination of tumor cells. Natural killer (NK) cells are members of innate immunity and represent powerful anti-tumor effectors, able to eliminate tumor cells without a previous sensitization. Thus, the study of their involvement in anti-tumor responses is critical for clinical translation. This analysis has been performed in vitro, co-incubating NK with tumor cells and quantifying the cytotoxic activity of NK cells. In vivo confirmation has been applied to overcome the limits of in vitro testing, however, the innate immunity of mice and humans is different, leading to discrepancies. Different activating receptors on NK cells and counter-ligands on tumor cells are involved in the antitumor response, and innate immunity is strictly dependent on the specific microenvironment where it takes place. Thus, three-dimensional (3D) culture systems, where NK and tumor cells can interact in a tissue-like architecture, have been created. For example, tumor cell spheroids and primary organoids derived from several tumor types, have been used so far to analyze innate immune response, replacing animal models. Herein, we briefly introduce NK cells and analyze and discuss in detail the properties of 3D tumor culture systems and their use for the study of tumor cell interactions with NK cells.

“…Indeed, a poor susceptibility to the NK-cellmediated killing of NB cell lines is associated with the presence of p53 mutations displayed by NB-MSC cells [62]. Moreover, Nutlin-3a, a compound that antagonizes the interaction between MDM2 and p53, may restore p53 transcription factor function, with a consequent increasing expression of ligands for NK cell-activating receptors on NB cells, enhancing the NK cell-mediated killing both in vitro and in vivo [63]. increasing expression of ligands for NK cell-activating receptors on NB cells, enhancing the NK cell-mediated killing both in vitro and in vivo [63].…”

Section: Neuroblastoma Cancer Cellsmentioning

confidence: 99%

Pediatric Tumors-Mediated Inhibitory Effect on NK Cells: The Case of Neuroblastoma and Wilms’ Tumors

Pelosi

Fiore

Matteo

et al. 2021

Self Cite

Natural killer (NK) cells play a key role in the control of cancer development, progression and metastatic dissemination. However, tumor cells develop an array of strategies capable of impairing the activation and function of the immune system, including NK cells. In this context, a major event is represented by the establishment of an immunosuppressive tumor microenvironment (TME) composed of stromal cells, myeloid-derived suppressor cells, tumor-associated macrophages, regulatory T cells and cancer cells themselves. The different immunoregulatory cells infiltrating the TME, through the release of several immunosuppressive molecules or by cell-to-cell interactions, cause an impairment of the recruitment of NK cells and other lymphocytes with effector functions. The different mechanisms by which stromal and tumor cells impair NK cell function have been particularly explored in adult solid tumors and, in less depth, investigated and discussed in a pediatric setting. In this review, we will compare pediatric and adult solid malignancies concerning the respective mechanisms of NK cell inhibition, highlighting novel key data in neuroblastoma and Wilms’ tumor, two of the most frequent pediatric extracranial solid tumors. Indeed, both tumors are characterized by the presence of stromal cells acting through the release of immunosuppressive molecules. In addition, specific tumor cell subsets inhibit NK cell cytotoxic function by cell-to-cell contact mechanisms likely controlled by the transcriptional coactivator TAZ. These findings could lead to a more performant diagnostic approach and to the development of novel immunotherapeutic strategies targeting the identified cellular and molecular targets.