| First Author | Serrels B | Year | 2017 |
| Journal | Sci Signal | Volume | 10 |
| Issue | 508 | PubMed ID | 29208683 |
| Mgi Jnum | J:259095 | Mgi Id | MGI:6140958 |
| Doi | 10.1126/scisignal.aan8355 | Citation | Serrels B, et al. (2017) IL-33 and ST2 mediate FAK-dependent antitumor immune evasion through transcriptional networks. Sci Signal 10(508) |
| abstractText | 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 kappaB (NF-kappaB) 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. |
