Type I IFN contributes to NK cell homeostasis, activation, and antitumor function.
This study demonstrates that type I IFNs are an early and critical regulator of NK cell numbers, activation, and antitumor activity. Using both IFNAR1- and IFNAR2-deficient mice, as well as an IFNAR1-blocking Ab, we demonstrate that endogenous type I IFN is critical for controlling NK cell-mediated antitumor responses in many experimental tumor models, including protection from methylcholanthrene-induced sarcomas, resistance to the NK cell-sensitive RMA-S tumor and cytokine immunotherapy of lung metastases. Protection from RMA-S afforded by endogenous type I IFN is more potent than that of other effector molecules such as IFN-gamma, IL-12, IL-18, and perforin. Furthermore, cytokine immunotherapy using IL-12, IL-18, or IL-21 was effective in the absence of endogenous type I IFN, however the antimetastatic activity of IL-2 was abrogated in IFNAR-deficient mice, primarily due to a defect in IL-2-induced cytotoxic activity. This study demonstrates that endogenous type I IFN is a central mediator of NK cell antitumor responses.
Swann
Jeremy B
JB
Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 8006 Victoria, Australia.
Hayakawa
Yoshihiro
Y
Zerafa
Nadeen
N
Sheehan
Kathleen C F
KC
Scott
Bernadette
B
Schreiber
Robert D
RD
Hertzog
Paul
P
Smyth
Mark J
MJ
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016207:Cytokines / Q000627:therapeutic use; D006706:Homeostasis; D007167:Immunotherapy; D007370:Interferon Type I / Q000502:physiology* / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D009369:Neoplasms / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000906:Antibodies; D016207:Cytokines; C508032:Ifnar1 protein, mouse; C508034:Ifnar2 protein, mouse; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta