title: Drug-induced hyperploidy stimulates an antitumor NK cell response mediated by NKG2D and DNAM-1 receptors.
abstract: Formation of polyploid or aneuploid cells is a pathological hallmark of malignant tumors. Cell cycle checkpoint mechanisms play a crucial role in ensuring genomic integrity during mitosis, avoiding the generation of aneuploid cells. Additionally, cancer cell DNA ploidy is subjected to extrinsic controls operated by activation of adaptive immune responses mediated by T cells. NK cells exert a central role in the innate anticancer immunity; however, the mechanisms involved in the recognition of tumor cells by NK cells have not been fully elucidated. Herein, we report that drug-induced polyploidy in cancer cells activates antitumor responses mediated by NK cells. Thus, hyperploidy-inducing chemotherapeutic agents strongly upregulate the tumor expression of ligands for the NK cell activating receptors NKG2D and DNAM-1. Drug-induced hyperploidy modulated the repertoire of activating receptors and the cytokine profile of NK cells, rendering tumor cells more susceptible to NK cell-mediated lysis through the activation of NKG2D and DNAM-1 receptors. In addition, hyperploidization stimulated the production of IL-2 by CD4 T cells, which induced NK cell proliferation and activity. The stimulation of MICA, a key NKG2D ligand, in hyperploid cells was mainly mediated by ATM protein kinase. Likewise, pharmacological inhibition of key regulators of endoplasmic reticulum stress in certain cell models supports a role for this pathway in NKG2D ligand upregulation. Overall, our findings indicate that, besides the cytotoxic effect on tumor cells, the therapeutic activity of anti-mitotic drugs may be mediated by the induction of a coordinated antitumor immune response involving NK and T cells.
authors.affiliation: Departamento de Biología Funcional, Inmunología, IUOPA, Universidad de Oviedo , Oviedo, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Acebes-Huerta
authors.affiliation: Departamento de Biología Funcional, Inmunología, IUOPA, Universidad de Oviedo , Oviedo, Spain.
authors.forename: Seila
authors.initials: S
authors.lastname: Lorenzo-Herrero
authors.affiliation: Departamento de Bioquímica y Biología Molecular, IUOPA, Universidad de Oviedo , Oviedo, Spain.
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Folgueras
authors.affiliation: Departamento de Biología Funcional, Inmunología, IUOPA, Universidad de Oviedo , Oviedo, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: Huergo-Zapico
authors.affiliation: Departamento de Biología Funcional, Inmunología, IUOPA, Universidad de Oviedo, Oviedo, Spain; Departamento de Inmunología, Hospital Universitario Central de Asturias, Oviedo, Spain; Fundación Renal Iñigo Álvarez de Toledo, Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopez-Larrea
authors.affiliation: Departamento de Biología Funcional, Inmunología, IUOPA, Universidad de Oviedo, Oviedo, Spain; Departamento de Inmunología, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: López-Soto
authors.affiliation: Departamento de Biología Funcional, Inmunología, IUOPA, Universidad de Oviedo , Oviedo, Spain.
authors.forename: Segundo
authors.initials: S
authors.lastname: Gonzalez
keywords: ATM; Calreticulin; DNA damage; DNAM-1; ER stress; MICA; NKG2D; T cells; cancer immunosurveillance; hyperploidy; natural killer cells