IL-33 and ST2 mediate FAK-dependent antitumor immune evasion through transcriptional networks

Bryan Serrels (Lead / Corresponding author), Niamh McGivern, Marta Canel, Adam Byron, Sarah C. Johnson, Henry J. McSorley, Niall Quinn, David Taggart, Alex Von Kreigsheim, Stephen M. Anderton, Alan Serrels (Lead / Corresponding author), Margaret C. Frame (Lead / Corresponding author)

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22 Citations (Scopus)

Abstract

Focal adhesion kinase (FAK) mediates tumor cell-intrinsic behaviors that promote tumor growth and metastasis. We previously showed that FAK also induces the expression of inflammatory genes that inhibit antitumor immunity in the microenvironment. We identified a crucial, previously unknown role for the dual-function cytokine interleukin-33 (IL-33) in FAK-dependent immune evasion. In murine squamous cell carcinoma (SCC) cells, specifically nuclear FAK enhanced the expression of the genes encoding IL-33, the chemokine CCL5, and the soluble, secreted form of the IL-33 receptor, called soluble ST2 (sST2). The abundance of IL-33 and CCL5 was increased in FAK-positive SCC cells but not in normal keratinocytes. IL-33 associated with FAK in the nucleus, and the FAK-IL-33 complex interactedwith a network of chromatinmodifiers and transcriptional regulators, including TAF9, WDR82, and BRD4, which promote the activity of nuclear factor kB (NF-kB) and its induction of genes encoding chemokines, including CCL5.We did not detect secretion of IL-33 from FAK-positive SCC cells; thus, we propose that the increased production and secretion of sST2 likely sequesters IL-33 secreted by other cell types within the tumor environment, thus blocking its stimulatory effects on infiltrating host immune cells. Depleting FAK, IL-33, or sST2 from SCC cells before implantation induced tumor regression in syngeneic mice, except when CD8+ T cells were co-depleted. Our data provide mechanistic insight into how FAK controls the tumor immune environment, namely, through a transcriptional regulatory network mediated by nuclear IL-33. Targeting this axis may boost antitumor immunity in patients.

Original languageEnglish
Article numbereaan8355
Pages (from-to)1-13
Number of pages13
JournalScience Signaling
Volume10
Issue number508
DOIs
Publication statusPublished - 5 Dec 2017

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    Serrels, B., McGivern, N., Canel, M., Byron, A., Johnson, S. C., McSorley, H. J., Quinn, N., Taggart, D., Von Kreigsheim, A., Anderton, S. M., Serrels, A., & Frame, M. C. (2017). IL-33 and ST2 mediate FAK-dependent antitumor immune evasion through transcriptional networks. Science Signaling, 10(508), 1-13. [eaan8355]. https://doi.org/10.1126/scisignal.aan8355