Colorectal Cancer microenvironment controls Mast Cell phenotypical plasticity

Purpose: Mast cells (MCs) are tissue-resident immune cells characterized by their cytoplasmic granules containing different proteases and by the surface expression of the high-affinity receptor for IgE (FcεRI) and c-kit (CD117), the receptor for stem cell factor (SCF). Once activated, MCs released several mediators and can orchestrate different immune responses in both physiological and pathological conditions including cancer. In particular, MCs can infiltrate Colorectal Cancer (CRC) but the precise role of mucosal versus connective-like intestinal MC subsets during CRC development is still unclear. The aim of our study is to investigate whether a particular MC subset is involved in CRC progression and to analyse how tumor microenvironment shapes MC plasticity. Methods: We employed a mouse model of chemical-induced inflammatory colorectal cancer (AOM/DSS) as well as tumor biopsies of CRC patients. We initially performed microscopic and flow cytometric analyses in order to study MC frequency, localization and phenotype. We further investigated by in vitro and in vivo assays the contribution of soluble factor enriched in tumor microenvironment in shaping murine MC plasticity. Results: By evaluating the expression of selective proteases within the granules of tumor infiltrating MCs, we demonstrated the prevalence of a connective tissue-like phenotype in both murine and human samples. Focusing on the tumor microenvironment of AOM/DSS-treated mice, we found a higher concentration of SCF and IL-33 in tumor lesions compared with tumor-free tissue. Moreover, we demonstrated that a sustained in vitro stimulation of MC primary cultures with SCF and IL-33 promotes the expansion of a connective-like MC subset. Consequently, trough in vivo experiments we observed that SCF-neutralization induce a decrease of the connective tissue-like MC subset accompanied by inhibition of tumor burden. Conclusion: Our results demonstrate that connective tissue-like MCs accumulate in both murine and human colorectal cancer lesions supporting a role for this subset in the control of tumor progression. Moreover, we underscored the ability of SCF in combination with IL-33 to shape MC phenotype.