Cord blood natural killer cells expressing a dominant negative TGF-β receptor: Implications for adoptive immunotherapy for glioblastoma

Yvon, Eric; Burga, Rachel A.; Powell, Allison B.; Cruz, Conrad Russell Y.; Fernandes, Rohan; Barese, Cecilia; Nguyen, Tuongvan; AbdelBaki, Mohamed S.; Bollard, Catherine M.

doi:10.1016/j.jcyt.2016.12.005

Cited by 107 publications

(76 citation statements)

References 39 publications

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“…This suggests that by blocking the interaction between NK cells and TGFβ we might be able to protect their metabolism and function in TGFβ rich environments, such as those found in cancer. For example, Yvon et al engrafted a dominant-negative TGFβR2 onto cord blood derived NK cells, leaving them resistant to the inhibitory effects of TGFβ treatment and more efficient at killing glioblastoma tumor cells (98). This was also shown to FIGURE 4 | NK cell immunotherapy.…”

Section: Nk Cell Immunotherapymentioning

confidence: 99%

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

Slattery

Gardiner

2019

Front. Immunol.

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NK cells are innate lymphocytes which play an essential role in protection against cancer and viral infection. Their functions are dictated by many factors including the receptors they express, cytokines they respond to and changes in the external environment. These cell processes are regulated within NK cells at many levels including genetic, epigenetic and expression (RNA and protein) levels. The last decade has revealed cellular metabolism as another level of immune regulation. Specific immune cells adopt metabolic configurations that support their functions, and this is a dynamic process with cells undergoing metabolic reprogramming during the course of an immune response. Upon activation with pro-inflammatory cytokines, NK cells upregulate both glycolysis and oxphos metabolic pathways and this supports their anti-cancer functions. Perturbation of these pathways inhibits NK cell effector functions. Anti-inflammatory cytokines such as TGFβ can inhibit metabolic changes and reduce functional outputs. Although a lot remains to be learned, our knowledge of potential molecular mechanisms involved is growing quickly. This review will discuss our current knowledge on the role of TGFβ in regulating NK cell metabolism and will draw on a wider knowledge base regarding TGFβ regulation of cellular metabolic pathways, in order to highlight potential ways in which TGFβ might be targeted to contribute to the exciting progress that is being made in terms of adoptive NK cell therapies for cancer.

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Section: Nk Cell Immunotherapymentioning

confidence: 99%

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

Slattery

Gardiner

2019

Front. Immunol.

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“…Blockade of T-cell responses to immunosuppressive cytokines may also improve immunotherapy potency. One such strategy provided resistance to TGF-ß by overexpressing a dominant negative TGF-β receptor in EBV-specific T-cells [64,65]. This dominant negative receptor bound TGF-β and n only provided T-cell resistance to the cytokine, but also served as a physiologic sink that prevented TGF-β from interacting with functional TGF-β receptors on other cells [64].…”

Section: Engineering T-cells To Combat the Immunosuppressive Tumor MImentioning

confidence: 99%

Strategies for enhancing adoptive T-cell immunotherapy against solid tumors using engineered cytokine signaling and other modalities

Shum

Kruse²,

Rooney³

2018

Expert Opinion on Biological Therapy

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Introduction: Cancer therapy has been transformed by the demonstration that tumor-specific T-cells can eliminate tumor cells in a clinical setting with minimal long-term toxicity. However significant success in the treatment of leukemia and lymphoma with T-cells using native receptors or redirected with chimeric antigen receptors (CARs) has not been recapitulated in the treatment of solid tumors. This lack of success is likely related to the paucity of costimulatory and cytokine signaling available in solid tumors, in addition to a range of inhibitory mechanisms. Areas covered: We summarize the latest developments in engineered T-cell immunotherapy, describe the limitations of these approaches in treating solid tumors, and finally highlight several strategies that may be useful in mediating solid tumor responses in the future, while also ensuring safety of engineered cells. Expert opinion: CAR-T therapies require further engineering to achieve their potential against solid tumors. Facilitating cytokine signaling in CAR T-cells appears to be essential in achieving better responses. However, the engineering of T-cells with potentially unchecked proliferation and potency raises the question of whether the simultaneous combination of enhancements will prove safe, necessitating continued advancements in regulating CAR-T activity at the tumor site and methods to safely switch off these engineered cells.

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“…Importantly, Galunisertib therapy could restore NKG2D and NKp30 expression on activated NK cells and enhanced NK cell cytotoxicity. Knockdown of TGFBR2 or SMAD3 in NK cells, engineering CB NK cells to express TGF-β dominant negative receptor II, or modifying NK cells using CAR containing TGF-β type II receptor extracellular and transmembrane domains, and the intracellular domain of NKG2D, are all under investigation and have shown great promise for the recovery of tumorsuppressed NK cell antitumor activity to treat patients with solid tumors (129)(130)(131).…”

Section: Other Strategies To Overcome the Suppression By The Tumor MImentioning

confidence: 99%

Targeting Natural Killer Cells for Tumor Immunotherapy

Zhang

Shi

2020

Front. Immunol.

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Natural killer (NK) cells are important innate cytotoxic lymphocytes with a rapid and efficient capacity to recognize and kill tumor cells. In recent years, adoptive transfer of autologous-or allogeneic-activated NK cells has become a promising cellular therapy for cancer. However, the therapeutic efficiency is encouraging in hematopoietic malignancies, but disappointing in solid tumors, for which the use of NK-cell-based therapies presents considerable challenges. It is difficult for NK cells to traffic to, and infiltrate into, tumor sites. NK cell function, phenotype, activation, and persistence are impaired by the tumor microenvironment, even leading to NK cell dysfunction or exhaustion. Many strategies focusing on improving NK cells' durable persistence, activation, and cytolytic activity, including activation with cytokines or analogs, have been attempted. Modifying them with chimeric antigen receptors further increases the targeting specificity of NK cells. Checkpoint blockades can relieve the exhausted state of NK cells. In this review, we discuss how the cytolytic and effector functions of NK cells are affected by the tumor microenvironment and summarize the various immunotherapeutic strategies based on NK cells. In particular, we discuss recent advances in overcoming the suppressive effect of the tumor microenvironment with the aim of enhancing the clinical outcome in solid tumors treated with NK-cell-based immunotherapy.

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Cord blood natural killer cells expressing a dominant negative TGF-β receptor: Implications for adoptive immunotherapy for glioblastoma

Cited by 107 publications

References 39 publications

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

Strategies for enhancing adoptive T-cell immunotherapy against solid tumors using engineered cytokine signaling and other modalities

Targeting Natural Killer Cells for Tumor Immunotherapy

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