OncoImmunology (Jan 2021)

CD34+ progenitor-derived NK cell and gemcitabine combination therapy increases killing of ovarian cancer cells in NOD/SCID/IL2Rgnull mice

  • Jolien M.R. Van der Meer,
  • Paul K.J.D. de Jonge,
  • Anniek B. van der Waart,
  • Alexander C. Geerlings,
  • Jurgen P. Moonen,
  • Jolanda Brummelman,
  • Janne de Klein,
  • Malou C. Vermeulen,
  • Ralph J.A. Maas,
  • Nicolaas P.M. Schaap,
  • Janneke S. Hoogstad-van Evert,
  • Petronella B. Ottevanger,
  • Joop H. Jansen,
  • Willemijn Hobo,
  • Harry Dolstra

DOI
https://doi.org/10.1080/2162402X.2021.1981049
Journal volume & issue
Vol. 10, no. 1

Abstract

Read online

Combining natural killer (NK) cell adoptive transfer with tumor-sensitizing chemotherapy is an attractive approach against recurrent ovarian cancer (OC), as OC is sensitive to NK cell-mediated immunity. Previously, we showed that CD34+ hematopoietic progenitor cell (HPC)-derived NK cells can kill OC cells in vitro and inhibit OC tumor growth in mice. Here, we investigated the potential of HPC-NK cell therapy combined with chemotherapeutic gemcitabine (used in recurrent OC patients) against OC. We examined the phenotypical, functional, and cytotoxic effects of gemcitabine on HPC-NK cells and/or OC cells in vitro and in OC-bearing mice. To this end, we treated OC cells and/or HPC-NK cells with or without gemcitabine and analyzed the phenotype, cytokine production, and anti-tumor reactivity. We found that gemcitabine did not affect the phenotype and functionality of HPC-NK cells, while on OC cells expression of NK cell activating ligands and death receptors was upregulated. Although gemcitabine pre-treatment of OC cells did not improve the functionality of HPC-NK cells, importantly, HPC-NK cells and gemcitabine additively killed OC cells in vitro. Similarly, combined HPC-NK cell and gemcitabine treatment additively decreased tumor growth in OC-bearing mice. Collectively, our results indicate that combination therapy of HPC-NK cells and gemcitabine results in augmented OC killing in vitro and in vivo. This provides a rationale for exploring this therapeutic strategy in patients with recurrent OC.

Keywords