IL1α Antagonizes IL1β and Promotes Adaptive Immune Rejection of Malignant Tumors

• Published in: Cancer immunology research 2020-05, Vol.8 (5), p.660-671
• Main Authors: Tian, Tian, Lofftus, Serena, Pan, Youdong, Stingley, Claire A, King, Sandra L, Zhao, Jingxia, Pan, Timothy Y, Lock, Rebecca, Marglous, Jacob W, Liu, Kevin, Widlund, Hans R, Fuhlbrigge, Robert C, Cichowski, Karen, Kupper, Thomas S
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Animals; Antibodies, Monoclonal - pharmacology; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Disease Models, Animal; Interleukin-1alpha - immunology; Interleukin-1alpha - metabolism; Interleukin-1beta - immunology; Interleukin-1beta - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, SCID; Neoplasms - immunology; Neoplasms - therapy; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Tumor Microenvironment
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.CIR-19-0552

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.