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This article is part of the Research Topic

Lymphocyte Functional Crosstalk and Regulation

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.00014

CD56dim CD16- Natural Killer Cell Profiling in Melanoma Patients Receiving a Cancer Vaccine and Interferon-α

 Lazar Vujanovic1, 2, Christopher Chuckran3, Yan Lin1, 4, Fei Ding1, 4, Cindy A. Sander1, 2, Patricia M. Santos1, 2, Joel Lohr3, Afshin Mashadi-Hossein5,  Sarah Warren5, Andrew White5, Alan Huang5,  John M. Kirkwood1, 2 and  Lisa H. Butterfield1, 2, 3, 6*
  • 1UPMC Hillman Cancer Center, United States
  • 2Department of Medicine, School of Medicine, University of Pittsburgh, United States
  • 3Department of Immunology, School of Medicine, University of Pittsburgh, United States
  • 4Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, United States
  • 5NanoString Technologies, United States
  • 6Department of Surgery, School of Medicine, University of Pittsburgh, United States

Natural killer (NK) cells are innate cytotoxic and immunoregulatory lymphocytes that have a central role in anti-tumor immunity and play a critical role in mediating cellular immunity in advanced cancer immunotherapies, such as dendritic cell (DC) vaccines. Our group recently tested a novel recombinant adenovirus-transduced autologous DC-based vaccine that simultaneously induces T cell responses against three melanoma-associated antigens for advanced melanoma patients. Here, we examine the impact of this vaccine as well as the subsequent systemic delivery of high-dose interferon-α2b (HDI) on the circulatory NK cell profile in melanoma patients. At baseline, patient NK cells, particularly those isolated from high-risk patients with no measurable disease, showed altered distribution of CD56dim CD16+ and CD56dim CD16- NK cell subsets, as well as elevated serum levels of immune suppressive MICA, TN5E/CD73 and tactile/CD96, and perforin. Surprisingly, patient NK cells displayed a higher level of activation than those from healthy donors as measured by elevated CD69, NKp44 and CCR7 levels, and enhanced K562 killing. Elevated cytolytic ability strongly correlated with increased representation of CD56dim CD16+ NK cells and amplified CD69 expression on CD56dim CD16+ NK cells. While intradermal DC immunizations did not significantly impact circulatory NK cell activation and distribution profiles, subsequent HDI injections enhanced CD56bright CD16- NK cell numbers when compared to patients that did not receive HDI. Phenotypic analysis of tumor-infiltrating NK cells showed that CD56dim CD16- NK cells are the dominant subset in melanoma tumors. NanoString transcriptomic analysis of melanomas resected at baseline indicated that there was a trend of increased CD56dim NK cell gene signature expression in patients with better clinical response. These data indicate that melanoma patient blood NK cells display elevated activation levels, that intra-dermal DC immunizations did not effectively promote systemic NK cell responses, that systemic HDI administration can modulate NK cell subset distributions and suggest that CD56dim CD16- NK cells are a unique non-cytolytic subset in melanoma patients that may associate with better patient outcome.

Keywords: Melanoma, Natural killer cells (NK cells), CD56dim CD16- NK cells, Dendritic Cells (DC), recombinant adenoviral vectors, Interferon-alpha treatment, immune check point, PD-1, TIGIT, CD69, NKp30, NKp44, CXCR1, CXCR3, CCR7, ANK-1

Received: 24 Aug 2018; Accepted: 04 Jan 2019.

Edited by:

Anil Shanker, Meharry Medical College, United States

Reviewed by:

Nathalie Jacobs, University of Liège, Belgium
R. Keith Reeves, Harvard Medical School, United States  

Copyright: © 2019 Vujanovic, Chuckran, Lin, Ding, Sander, Santos, Lohr, Mashadi-Hossein, Warren, White, Huang, Kirkwood and Butterfield. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Lisa H. Butterfield, UPMC Hillman Cancer Center, Pittsburgh, 15232, Pennsylvania, United States,