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The role of interleukin-2, all-trans retinoic acid, and natural killer cells: surveillance mechanisms in anti-GD2 antibody therapy in neuroblastoma

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Abstract

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.

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Abbreviations

ADCC:

Antibody-dependent cell-mediated cytotoxicity

ATRA:

All-trans retinoic acid

E:T:

Effector cell to target cell

EMEM:

Eagle’s minimum essential medium

GD2:

Disialoganglioside

HLA:

Human leukocyte antigen

IL-2:

Interleukin-2

KIR:

Killer-cell immunoglobulin-like receptor

NK:

Natural killer

O-PDX:

Orthotopic patient-derived xenograft

rIL-2:

Recombinant interleukin-2

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Acknowledgements

We thank Merck Serono and the Children’s GMP, LLC for providing the Hu14.18K322A anti-GD2 antibody to conduct our studies. We also thank the Biological Resource Branch at the National Cancer Institute for providing rIL-2 used in the present study. We thank Drs. Jennifer Peters and Abbas Shirinifard for optimizing the automated microscopy protocol and optimizing the classifier for segmentation purposes in Fiji, respectively. We thank Dr. Dan Kaufman for reviewing the manuscript. We thank Nisha Badders for scientific editing.

Funding

This work was supported, in part, by Cancer Center Support (CA21765) from the NCI, grants to M.A.D. from the NIH (EY014867 and EY018599 and CA168875). This research was supported by HHMI.

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Authors and Affiliations

  1. Department of Oncology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA

    Rosa Nguyen

  2. Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA

    Jim Houston & Michael A. Dyer

  3. The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA

    Wing K. Chan

  4. Department of Computational Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA

    David Finkelstein

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  1. Rosa Nguyen
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  4. David Finkelstein
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  5. Michael A. Dyer
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Contributions

RN: experimental design, conduction of experiments, analysis and interpretation of data, draft of the manuscript. JH: experimental design, conduction of flow cytometry experiments, review of the manuscript. WKC: experimental design, interpretation of data, review of the manuscript. DF: analysis of RNA sequencing data, review of the manuscript. MAD: experimental design, analysis and interpretation of data, review of manuscript, funding.

Corresponding author

Correspondence to Michael A. Dyer.

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The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

Patient consented to donate biological material (blood and tumor) as part of an ongoing institutional protocol XPD09-234 MAST—MOLECULAR ANALYSIS OF SOLID TUMORS. This protocol was approved by the St. Jude Children’s Research Hospital IRB.

Animal source

All animals were handled according to IACUC approved policies.

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Nguyen, R., Houston, J., Chan, W.K. et al. The role of interleukin-2, all-trans retinoic acid, and natural killer cells: surveillance mechanisms in anti-GD2 antibody therapy in neuroblastoma. Cancer Immunol Immunother 67, 615–626 (2018). https://doi.org/10.1007/s00262-017-2108-6

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