Engineering the TGFβ Receptor to Enhance the Therapeutic Potential of Natural Killer Cells as an Immunotherapy for Neuroblastoma

Clin Cancer Res. 2019 Jul 15;25(14):4400-4412. doi: 10.1158/1078-0432.CCR-18-3183. Epub 2019 Apr 22.


Purpose: The ability of natural killer (NK) cells to lyse allogeneic targets, without the need for explicit matching or priming, makes them an attractive platform for cell-based immunotherapy. Umbilical cord blood is a practical source for generating banks of such third-party NK cells for "off-the-shelf" cell therapy applications. NK cells are highly cytolytic, and their potent antitumor effects can be rapidly triggered by a lack of HLA expression on interacting target cells, as is the case for a majority of solid tumors, including neuroblastoma. Neuroblastoma is a leading cause of pediatric cancer-related deaths and an ideal candidate for NK-cell therapy. However, the antitumor efficacy of NK cells is limited by immunosuppressive cytokines in the tumor microenvironment, such as TGFβ, which impair NK cell function and survival.

Experimental design: To overcome this, we genetically modified NK cells to express variant TGFβ receptors, which couple a mutant TGFβ dominant-negative receptor to NK-specific activating domains. We hypothesized that with these engineered receptors, inhibitory TGFβ signals are effectively converted to activating signals.

Results: Modified NK cells exhibited higher cytotoxic activity against neuroblastoma in a TGFβ-rich environment in vitro and superior progression-free survival in vivo, as compared with their unmodified controls.

Conclusions: Our results support the development of "off-the-shelf" gene-modified NK cells, that overcome TGFβ-mediated immune evasion, in patients with neuroblastoma and other TGFβ-secreting malignancies.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / immunology
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Female
  • Genetic Engineering*
  • Humans
  • Immunotherapy / methods*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Male
  • Mice
  • Mice, Inbred NOD
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / immunology*
  • Neuroblastoma / pathology
  • Receptor, Transforming Growth Factor-beta Type II / genetics
  • Receptor, Transforming Growth Factor-beta Type II / immunology*
  • Receptor, Transforming Growth Factor-beta Type II / metabolism
  • Tumor Microenvironment / immunology*
  • Xenograft Model Antitumor Assays


  • Receptor, Transforming Growth Factor-beta Type II
  • TGFBR2 protein, human