IL1α Antagonizes IL1β and Promotes Adaptive Immune Rejection of Malignant Tumors
Tian Tian, Serena Lofftus, Youdong Pan, Claire A. Stingley, Sandra L. King, Jingxia Zhao, Timothy Y. Pan, Rebecca Lock, Jacob W. Marglous, Kevin Liu, Hans R. Widlund, Robert C. Fuhlbrigge, Karen Cichowski, Thomas S. Kupper
Abstract
Abstract We assessed the contribution of IL1 signaling molecules to malignant tumor growth using IL1β−/−, IL1α−/−, and IL1R1−/− mice. Tumors grew progressively in IL1R−/− and IL1α−/− mice but were often absent in IL1β−/− mice. This was observed whether tumors were implanted intradermally or injected intravenously and was true across multiple distinct tumor lineages. Antibodies to IL1β prevented tumor growth in wild-type (WT) mice but not in IL1R1−/− or IL1α−/− mice. Antibodies to IL1α promoted tumor growth in IL1β−/− mice and reversed the tumor-suppressive effect of anti-IL1β in WT mice. Depletion of CD8+ T cells and blockade of lymphocyte mobilization abrogated the IL1β−/− tumor suppressive effect, as did crossing IL1β−/− mice to SCID or Rag1−/− mice. Finally, blockade of IL1β synergized with blockade of PD-1 to inhibit tumor growth in WT mice. These results suggest that IL1β promotes tumor growth, whereas IL1α inhibits tumor growth by enhancing T-cell–mediated antitumor immunity.