PMID- 29327110 OWN - NLM STAT- MEDLINE DCOM- 20190228 LR - 20220129 IS - 1432-0851 (Electronic) IS - 0340-7004 (Print) IS - 0340-7004 (Linking) VI - 67 IP - 4 DP - 2018 Apr TI - The role of interleukin-2, all-trans retinoic acid, and natural killer cells: surveillance mechanisms in anti-GD2 antibody therapy in neuroblastoma. PG - 615-626 LID - 10.1007/s00262-017-2108-6 [doi] AB - Although anti-disialoganglioside (GD2) antibodies are successfully used for neuroblastoma therapy, a third of patients with neuroblastoma experience treatment failure or serious toxicity. Various strategies have been employed in the clinic to improve antibody-dependent cell-mediated cytotoxicity (ADCC), such as the addition of interleukin (IL)-2 to enhance natural killer (NK) cell function, adoptive transfer of allogeneic NK cells to exploit immune surveillance, and retinoid-induced differentiation therapy. Nevertheless, these mechanisms are not fully understood. We developed a quantitative assay to test ADCC induced by the anti-GD2 antibody Hu14.18K322A in nine neuroblastoma cell lines and dissociated cells from orthotopic patient-derived xenografts (O-PDXs) in culture. IL-2 improved ADCC against neuroblastoma cells, and differentiation with all-trans retinoic acid stabilized GD2 expression on tumor cells and enhanced ADCC as well. Degranulation was highest in licensed NK cells that expressed CD158b (P < 0.001) and harbored a killer-cell immunoglobulin-like receptor (KIR) mismatch against the tumor-specific human leukocyte antigen (HLA; P = 0.016). In conclusion, IL-2 is an important component of immunotherapy because it can improve the cytolytic function of NK cells against neuroblastoma cells and could lower the antibody dose required for efficacy, thereby reducing toxicity. The effect of IL-2 may vary among individuals and a biomarker would be useful to predict ADCC following IL-2 activation. Sub-populations of NK cells may have different levels of activity dependent on their licensing status, KIR expression, and HLA-KIR interaction. Better understanding of HLA-KIR interactions and the molecular changes following retinoid-induced differentiation is necessary to delineate their role in ADCC. FAU - Nguyen, Rosa AU - Nguyen R AD - Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. FAU - Houston, Jim AU - Houston J AD - Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. FAU - Chan, Wing K AU - Chan WK AD - The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. FAU - Finkelstein, David AU - Finkelstein D AD - Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. FAU - Dyer, Michael A AU - Dyer MA AD - Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. michael.dyer@stjude.org. LA - eng GR - HHMI_/Howard Hughes Medical Institute/United States GR - P30 CA021765/CA/NCI NIH HHS/United States GR - R01 CA219686/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20180111 PL - Germany TA - Cancer Immunol Immunother JT - Cancer immunology, immunotherapy : CII JID - 8605732 RN - 0 (Antibodies, Monoclonal) RN - 0 (Gangliosides) RN - 0 (Interleukin-2) RN - 5688UTC01R (Tretinoin) RN - 65988-71-8 (ganglioside, GD2) SB - IM MH - Antibodies, Monoclonal/*administration & dosage MH - Antibody-Dependent Cell Cytotoxicity/*immunology MH - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage MH - Combined Modality Therapy MH - Gangliosides/*immunology MH - Humans MH - Interleukin-2/administration & dosage MH - Killer Cells, Natural/*immunology MH - Neuroblastoma/immunology/pathology/*therapy MH - Tretinoin/administration & dosage MH - Tumor Cells, Cultured PMC - PMC5862751 MID - NIHMS934237 OTO - NOTNLM OT - Anti-GD2 antibody OT - IL-2 OT - Missing-self OT - NK cells OT - Neuroblastoma COIS- The authors declare that they have no conflict of interest. EDAT- 2018/01/13 06:00 MHDA- 2019/03/01 06:00 PMCR- 2018/01/11 CRDT- 2018/01/13 06:00 PHST- 2017/06/28 00:00 [received] PHST- 2017/12/14 00:00 [accepted] PHST- 2018/01/13 06:00 [pubmed] PHST- 2019/03/01 06:00 [medline] PHST- 2018/01/13 06:00 [entrez] PHST- 2018/01/11 00:00 [pmc-release] AID - 10.1007/s00262-017-2108-6 [pii] AID - 2108 [pii] AID - 10.1007/s00262-017-2108-6 [doi] PST - ppublish SO - Cancer Immunol Immunother. 2018 Apr;67(4):615-626. doi: 10.1007/s00262-017-2108-6. Epub 2018 Jan 11.