Interleukin 33 (IL-33) is a complex inflammatory cytokine with diverse functions. In the context of cancer development, depending on the model, the implementation and dosage, and the immune cells involved, IL-33 can elicit dramatically different outcomes. Recent studies, including our own, have explored definitive contributions of the adaptive immunity in IL-33-mediated antitumor effects. Innate immune involvement, however, has been poorly characterized. Utilizing Rag1-/- mice (lacking T and B lymphocytes), we show that either systemic administration of recombinant IL-33 or ectopic expression of IL-33 effectively inhibits tumor growth independent of adaptive antitumor immunity. We further demonstrate that IL-33-mediated antitumor effects depend on expansion and activation of NK cells. Additionally, IL-33 promotes the intratumoral expansion of active type 2 innate lymphoid cells (ILC2s) via its receptor, ST2. The role of ILC2s in cancer is almost entirely unexplored. Interestingly, IL-33-treated ILC2s exacerbated tumor growth. These ILC2s directly inhibited NK activation and cytotoxicity. IL-33-induced ILC2 activity coincided with greater expression of the immunosuppressive ecto-enzyme CD73. Absence of CD73 expression in ILC2s resulted in increased activation levels in NK cells, offering a potential mechanism by which ILC2s might suppress NK cell-mediated tumor killing. Thus, our data reveal a novel contribution of IL-33-induced ILC2 to tumor growth by weakening NK cell activation and tumor killing, regardless of adaptive immunity.

Creator

• Long, Alan Wyndham

DOI

• https://doi.org/10.21985/n2-ymsb-v968

Subject

• Oncology
• Immunology

Language

• en

Alternate Identifier

• etdadmin_upload_639294
• http://dissertations.umi.com/northwestern:14519

Keyword

• cancer immunology
• natural killer cells
• interleukin 33
• Innate lymphoid cells
• immunotherapy
• cd73

Date created

• 2019-01-01

Resource type

• Dissertation

Rights statement

• In Copyright