Augmentation of NK Cell Proliferation and Anti-tumor Immunity by Transgenic Expression of Receptors for Erythropoietin or Thrombopoietin

Abstract Many investigational adoptive immunotherapy regimens utilizing NK cells require the administration of IL-2 or IL-15 but these cytokines cause serious dose-dependent toxicities. To reduce or preclude the necessity for IL-2 use, we investigated whether genetic engineering of NK cells to express the erythropoietin receptor (EPOR) or thrombopoietin receptor (c-MPL) could be used as a method to improve NK cell survival and function. Viral transduction of NK-92 cells to express EPOR or c-MPL receptors conveyed signaling via appropriate pathways, protected cells from apoptosis, augmented cellular proliferation, and increased cell cytotoxic tumor function in response to erythropoietin (EPO) or thrombopoietin (TPO) ligands in vitro. In the presence of TPO, viral transduction of primary human NK cells to express c-MPL enhanced cellular proliferation and increased degranulation and cytokine production towards target cells in vitro. In contrast, transgenic expression of EPOR did not augment the proliferation of primary NK cells. In immunodeficient mice receiving TPO, in-vivo persistence of primary human NK cells genetically modified to express c-MPL was higher compared with control NK cells. These data support the concept that genetic manipulation of NK cells to express hematopoietic growth factor receptors could be used as strategy to augment NK cell proliferation and antitumor immunity.