SCF and IL-33 regulate mouse mast cell phenotypic and functional plasticity supporting a pro-inflammatory microenvironment

Mast cells (MCs) are multifaceted innate immune cells often present in the tumor microenvironment (TME). Several recent findings support their contribution to the transition from chronic inflammation to cancer. However, MC-derived mediators can either favor tumor progression, inducing the spread of the tumor, or exert anti-tumorigenic functions, limiting tumor growth. This apparent controversial role likely depends on the plastic nature of MCs that under different microenvironmental stimuli can rapidly change their phenotype and functions. Thus, the exact effect of unique MC subset(s) during tumor progression is far from being understood. Using a murine model of colitis-associated colorectal cancer, we initially characterized the MC population within the TME and in non-lesional colonic areas, by multicolor flow cytometry and confocal microscopy. Our results demonstrated that tumor-associated MCs harbor a main connective tissue phenotype and release high amounts of Interleukin (IL)-6 and Tumor Necrosis Factor (TNF)-alpha. This MC phenotype correlates with the presence of high levels of Stem Cell Factor (SCF) and IL-33 inside the tumor. Thus, we investigated the effect of SCF and IL-33 on primary MC cultures and underscored their ability to shape MC phenotype eliciting the production of pro-inflammatory cytokines. Our findings support the conclusion that during colonic transformation a sustained stimulation by SCF and IL-33 promotes the accumulation of a prevalent connective tissue-like MC subset that through the secretion of IL-6 and TNF-alpha maintains a pro-inflammatory microenvironment.

Automated summary

Mast cells (MCs) are innate immune cells that play a multifaceted role in the tumor microenvironment (TME). Recent studies have shown that MCs contribute to the transition from chronic inflammation to cancer. However, MC-derived mediators can either promote tumor progression or exert anti-tumorigenic effects, depending on the microenvironmental stimuli. This study focused on a specific subset of MCs in a murine model of colitis-associated colorectal cancer and found that these tumor-associated MCs have a connective tissue phenotype and release interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha. The presence of high levels of stem cell factor (SCF) and IL-33 in the tumor was found to shape the MC phenotype and promote the secretion of pro-inflammatory cytokines. This study highlights the importance of understanding the role of specific MC subsets in tumor progression.