Cancer-induced immunosuppression: IL-18-elicited immunoablative NK cells.

During cancer development, a number of regulatory cell subsets and immunosuppressive cytokines subvert adaptive immune responses. Although it has been shown that tumor-derived interleukin (IL)-18 participates in the PD-1-dependent tumor progression in NK cell-controlled cancers, the mechanistic cues underlying this immunosuppression remain unknown. Here, we show that IL-18 converts a subset of Kit(-) (CD11b(-)) into Kit(+) natural killer (NK) cells, which accumulate in all lymphoid organs of tumor bearers and mediate immunoablative functions. Kit(+) NK cells overexpressed B7-H1/PD-L1, a ligand for PD-1. The adoptive transfer of Kit(+) NK cells promoted tumor growth in two pulmonary metastases tumor models and significantly reduced the dendritic and NK cell pools residing in lymphoid organs in a B7-H1-dependent manner. Neutralization of IL-18 by RNA interference in tumors or systemically by IL-18-binding protein dramatically reduced the accumulation of Kit(+)CD11b(-) NK cells in tumor bearers. Together, our findings show that IL-18 produced by tumor cells elicits Kit(+)CD11b(-) NK cells endowed with B7-H1-dependent immunoablative functions in mice.
AuthorsMagali Terme, Evelyn Ullrich, Laetitia Aymeric, Kathrin Meinhardt, Jérôme D Coudert, Mélanie Desbois, François Ghiringhelli, Sophie Viaud, Bernard Ryffel, Hideo Yagita, Lieping Chen, Salaheddine Mécheri, Gilles Kaplanski, Armelle Prévost-Blondel, Masashi Kato, Joachim L Schultze, Eric Tartour, Guido Kroemer, Mariapia Degli-Esposti, Nathalie Chaput, Laurence Zitvogel
JournalCancer research (Cancer Res) Vol. 72 Issue 11 Pg. 2757-67 (Jun 1 2012) ISSN: 1538-7445 [Electronic] United States
PMID22427351 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright©2012 AACR
Chemical References
  • Antigens, CD11b
  • Antigens, CD274
  • Interleukin-18
  • Proto-Oncogene Proteins c-kit
  • Animals
  • Antigens, CD11b (analysis)
  • Antigens, CD274 (analysis, physiology)
  • Female
  • Interleukin-18 (immunology)
  • Killer Cells, Natural (immunology)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms (immunology)
  • Proto-Oncogene Proteins c-kit (analysis)

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