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

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. Here, we identified a crucial, previously unknown role for the dual-function cytokine 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 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 tumour immune environment, namely through a transcriptional regulatory network mediated by nuclear IL-33. Targeting this axis may boost antitumor immunity in patients.

Interleukin‐33‐nuclear factor‐κB‐CCL2 signaling pathway promotes progression of esophageal squamous cell carcinoma by directing regulatory T cells

“…[28][29][30] Here, we reported that IL-33 was upregulated in ESCC tissue sections, suggesting that IL-33 overexpression might be correlated with ESCC progress. Our results were confirmed by a recent study in murine squamous cell carcinoma cells, 19 indicating that IL-33 has a significant function in ESCC progression. In addition, functional analysis observed that IL-33 was significantly related with invasive depth, degree of differentiation, and TNM stage and a poorer survival rate.…”

“…17,18 A previous study found that IL-33 is restrictively expressed in murine squamous cell carcinoma cells, and it could activate FAK downstream to regulate CCL5 expression and tumor growth. 19 In this study, we aimed to examine the expression and function of IL-33 in ESCC and the underlying mechanism both in vitro and in vivo. Furthermore, the corresponding effect of IL-33 in regulating cell proliferation, cell cycle, migration, invasion, and clonogenicity were also explored.…”

“…Previous studies indicated that the IL‐33/ST2L axis could regulate inflammatory responses in many cancers, including ulcerative colitis, colitis‐associated cancer, and gastric cancer . A previous study found that IL‐33 is restrictively expressed in murine squamous cell carcinoma cells, and it could activate FAK downstream to regulate CCL5 expression and tumor growth . In this study, we aimed to examine the expression and function of IL‐33 in ESCC and the underlying mechanism both in vitro and in vivo.…”

A Synergistic Anti-Cancer FAK and HDAC Inhibitor Combination Discovered by a Novel Chemical-Genetic High-Content Phenotypic Screen

“…Cell lysates were prepared for immunoblotting and immunoprecipitation as previously described (3,7).…”

“…Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is frequently over-expressed in cancer, where it functions downstream of integrins and growth factor receptors to regulate a diverse range of cellular functions, including survival, proliferation, adhesion, migration, angiogenesis, stemness, and more recently, cytokine expression (1,2). FAK plays a pivotal role in transducing signals from the plasma membrane and the nucleus (2)(3)(4)(5)(6)(7)(8). It is recognized as a high-value druggable target for cancer therapy, resulting in the development of multiple FAK kinase inhibitors that are being tested in clinical trials (reviewed in Lee et al, (1)).…”