title: High-efficiency lysis of cervical cancer by allogeneic NK cells derived from umbilical cord progenitors is independent of HLA status.
abstract: Down-regulation of HLA in tumor cells, low numbers and dysfunctionality of NK cells are commonly observed in patients with end-stage cervical cancer. Adoptive transfer of high numbers of cytotoxic NK cells might be a promising treatment approach in this setting. Here, we explored the cytotoxic efficacy on ten cervical cancer cell lines of activated allogeneic NK cells from two sources, i.e., peripheral blood (PBNK) with and without cetuximab (CET), a tumor-specific monoclonal antibody directed against EGFR, or derived from umbilical cord blood (UCB-NK). Whereas CET monotherapy was ineffective against the panel of cervical cancer cell lines, irrespective of their EGFR expression levels and despite their RASwtstatus, it significantly enhanced the in vitro cytotoxic efficacy of activated PBNK (P = 0.002). Equally superior cytotoxicity over activated PBNK alone was achieved by UCB-NK (P < 0.001). Both PBNK- and UCB-NK-mediated cytotoxic activity was dependent on the NK-activating receptors natural killer group 2, member D receptor (NKG2D) and DNAX accessory molecule-1 (DNAM-1) (P < 0.05) and unrelated to expression levels of the inhibitory receptors HLA-E and/or HLA-G. Most strikingly, whereas the PBNK's cytotoxic activity was inversely correlated with HLA-ABC levels (P = 0.036), PBNK + CET and UCB-NK cytotoxicity were entirely independent of HLA-ABC expression. In conclusion, this study provides a rationale to initiate a clinical trial for cervical cancer with adoptively transferred allogeneic NK cells, employing either UCB-NK or PBNK + CET for EGFR-expressing tumors. Adoptive transfer of UCB-NK might serve as a generally applicable treatment for cervical cancer, enabled by HLA-, histology- and HPV-independent killing mechanisms.
authors: Department of Medical Oncology, VU (Vrije Universiteit) University Medical Center-Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.|Glycostem Therapeutics, Oss, The Netherlands.
authors: John P
authors: JP
authors: Veluchamy
authors: Department of Medical Oncology, VU (Vrije Universiteit) University Medical Center-Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.|Department of Obstetrics and Gynecology, Center Gynecological Oncology Amsterdam (CGOA), VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors: A Marijne
authors: AM
authors: Heeren
authors: Glycostem Therapeutics, Oss, The Netherlands.
authors: Jan
authors: J
authors: Spanholtz
authors: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
authors: Jaap D H
authors: JD
authors: van Eendenburg
authors: Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors: Daniëlle A M
authors: DA
authors: Heideman
authors: Department of Obstetrics and Gynecology, Center Gynecological Oncology Amsterdam (CGOA), VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors: Gemma G
authors: GG
authors: Kenter
authors: Department of Medical Oncology, VU (Vrije Universiteit) University Medical Center-Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors: Henk M
authors: HM
authors: Verheul
authors: Department of Medical Oncology, VU (Vrije Universiteit) University Medical Center-Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors: Hans J
authors: HJ
authors: van der Vliet
authors: Department of Obstetrics and Gynecology, Center Gynecological Oncology Amsterdam (CGOA), VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors: Ekaterina S
authors: ES
authors: Jordanova
authors: Department of Medical Oncology, VU (Vrije Universiteit) University Medical Center-Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. TD.deGruijl@vumc.nl.
authors: Tanja D
authors: TD
authors: de Gruijl
mesh_terms: D045744:Cell Line, Tumor; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology*; D010641:Phenotype; D014184:Transplantation, Homologous; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000628:therapy*
chemical_list: D006680:HLA Antigens
keywords: Adoptive NK immunotherapy; CET; Cervical cancer; NK ligands and receptors; Peripheral blood NK cells; Umbilical cord blood stem cell-derived NK cells