Connective tissue-like Mast Cells accumulate during Colorectal Cancer progression

Background: Mast cells (MCs) are tissue-resident immune cells characterized by their high granularity and by the surface expression of the high-affinity receptor for IgE (FcεRI) and CD117/KIT, the receptor for stem cell factor (SCF). Once activated, MCs can orchestrate immune responses through the release of several mediators. Interestingly, it has been recently shown that they can infiltrate Colorectal Cancer (CRC) where their density is correlated with cancer progression. However, the precise role of MCs during CRC development is still a matter of debate. Purpose: Our aim is dissecting phenotype and functions of MCs within tumor microenvironment. Results: We initially employed a mouse model of chemical-induced inflammatory CRC (AOM-DSS). By flow cytometric and microscopic analyses, we demonstrated that MCs accumulated within the tumor showed a connective tissue-like phenotype (CTMCs) and the capability to produce Tumor Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6). In human CRC lesions, we observed an increased frequency of MCs expressing both tryptase and chymase respect to the adjacent tumor-free tissue. We are currently establishing coculture systems with primary human MC cultures and CRC organoids to evaluate the role of tumor microenvironment on MC phenotypic and functional plasticity by assessing signature cytokines and effector molecules. Conclusions: CTMCs accumulate within murine tumor and by producing TNF- and IL-6 contribute to the establishment of inflammatory microenvironment. Moreover, connective tissue-like MCs infiltrate also human colon lesions, leading to the hypothesis that this subset may control tumor progression.