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Interleukin-15 in cancer immunotherapy: IL-15 receptor complex versus soluble IL-15 in a cancer cell-delivered murine leukemia model

Authors
  • Berger, Alexandra1
  • Colpitts, Sarah J.1, 2
  • Seabrook, Melanie S. S.1
  • Furlonger, Caren L.1
  • Bendix, Maura B.1
  • Moreau, Joshua M.1, 2, 3
  • McKillop, William M.1, 4
  • Medin, Jeffrey A.1, 4, 2
  • Paige, Christopher J.1, 2, 2
  • 1 University Health Network, 610 University Avenue, Room 8-105, Toronto, Ontario, M5G 2M9, Canada , Toronto (Canada)
  • 2 University of Toronto, Toronto, Canada , Toronto (Canada)
  • 3 University of California San Francisco, San Francisco, USA , San Francisco (United States)
  • 4 Medical College of Wisconsin, Milwaukee, USA , Milwaukee (United States)
Type
Published Article
Journal
Journal for ImmunoTherapy of Cancer
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Dec 19, 2019
Volume
7
Issue
1
Identifiers
DOI: 10.1186/s40425-019-0777-8
Source
Springer Nature
Keywords
License
Green

Abstract

Cytokines of the common γ-chain receptor family such as IL-15 are vital with respect to activating immune cells, sustaining healthy immune functions, and augmenting the anti-tumor activity of effector cells, making them ideal candidates for cancer immunotherapy. IL-15, either in its soluble form (IL-15sol) or complexed with IL-15Rα (IL-15Rc), has been shown to exhibit potent anti-tumor activities in various experimental cancer studies. Here we describe the impact of intraperitoneal IL-15 in a cancer cell-delivered IL-15 immunotherapy approach using the 70Z/3-L leukemia mouse model. Whereas both forms of IL-15 led to significantly improved survival rates compared to the parent cell line, there were striking differences in the extent of the improved survival: mice receiving cancer cells secreting IL-15sol showed significantly longer survival and protective long-term immunity compared to those producing IL-15Rc. Interestingly, injection of leukemia cells secreting IL-15sol lead to heightened expansion of CD4+ and CD8+ T-cell populations in the peritoneum compared to IL-15Rc. Cell-secreted IL-15Rc resulted in an influx and/or expansion of NK1.1+ cells in the peritoneum which was much less pronounced in the IL-15sol model. Furthermore, IL-15Rc but not IL-15sol lead to T-cell exhaustion and disease progression. To our knowledge, this is the first study detailing a significantly different biological effect of cell-delivered IL-15sol versus IL-15Rc in a mouse cancer immunotherapy study.

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