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

Bryan Serrels, Niamh McGivern, Marta Canel, Adam Byron, Sarah C. Johnson, Henry J. McSorley, Niall Quinn, David Taggart, Alex Von Kriegsheim, Stephen M. Anderton, Alan Serrels, Margaret C. Frame

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 interacted with a network of chromatin modifiers and transcriptional regulators, including TAF9, WDR82, and BRD4, which promote the activity of nuclear factor κB (NF-κB) 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
JournalScience Signaling
Issue number508
Publication statusPublished - 5 Dec 2017


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