Research ArticleCancer Immunology

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

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Science Signaling  05 Dec 2017:
Vol. 10, Issue 508, eaan8355
DOI: 10.1126/scisignal.aan8355

FAK directs tumor immune evasion

Tumors are adept at escaping the immune system’s surveillance or suppressing its activity. The kinase FAK is implicated in immune escape mechanisms. Serrels et al. found that FAK activates a transcriptional network that induces—and is then further mediated by—the nuclear abundance of interleukin-33 (IL-33) in tumor cells. In a mouse model of squamous cell carcinoma, FAK–IL-33 complexes boosted the production and secretion of two key factors in immunosuppression: the chemokine CCL5, which stimulates immunosuppressive regulatory T cells, and soluble ST2, a decoy receptor for cytotoxic T cell–stimulatory IL-33. Blocking these FAK-mediated signals may help the patient’s immune system find and kill tumors.


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.

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