Mast cell-T cell axis alters development of colitis-dependent and colitis-independent colorectal tumours: potential for therapeutically targeting via mast cell inhibition

Abstract

BackgroundColorectal cancer (CRC) has a high mortality rate and can develop in either colitis-dependent (colitis-associated (CA)-CRC) or colitis-independent (sporadic (s)CRC) manner. There has been a significant debate about whether mast cells (MCs) promote or inhibit the development of CRC. Herein we investigated MC activity throughout the multistepped development of CRC in both human patients and animal models.MethodsWe analyzed human patient matched samples of healthy colon vs CRC tissue alongside conducting a The Cancer Genome Atlas-based immunogenomic analysis and multiple experiments employing genetically engineered mouse (GEM) models.ResultsAnalyzing human CRC samples revealed that MCs can be active or inactive in this disease. An activated MC population decreased the number of tumor-residing CD8 T cells. In mice, MC deficiency decreased the development of CA-CRC lesions, while it increased the density of tumor-based CD8 infiltration. Furthermore, co-culture experiments revealed that tumor-primed MCs promote apoptosis in CRC cells. In MC-deficient mice, we found that MCs inhibited the development of sCRC lesions. Further exploration of this with several GEM models confirmed that different immune responses alter and are altered by MC activity, which directly alters colon tumorigenesis. Since rescuing MC activity with bone marrow transplantation in MC-deficient mice or pharmacologically inhibiting MC effects impacts the development of sCRC lesions, we explored its therapeutic potential against CRC. MC activity promoted CRC cell engraftment by inhibiting CD8+ cell infiltration in tumors, pharmacologically blocking it inhibits the ability of allograft tumors to develop. This therapeutic strategy potentiated the cytotoxic activity of fluorouracil chemotherapy.ConclusionTherefore, we suggest that MCs have a dual role throughout CRC development and are potential druggable targets against this disease.

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

“…However, there are also studies in which MCs appear to play a protective role in CRC tumorigenesis [ 47 – 49 ]. Notably, a recent work from Sakita and colleagues show that MCs could either promote or inhibit the development of colon tumors according to microenvironment stimuli, being tumorigenic in colitis-induced CRC and protective in murine models of sporadic CRC [ 50 ]. This finding well fits with the current view that during CRC development MC activity may impact either in a beneficial or harmful fashion depending on the genetic background of mice and the specific tumor models [ 51 ].…”

Asthma is associated with a lower incidence of metastatic colorectal cancer in a US patient cohort

“…The glucocorticoid receptor is the primary target for synthesized corticosteroids and it is unclear if activation of the glucocorticoid receptor is linked to increased or reduced metastatic potential in colorectal cancer ( 36 – 40 ). Additionally, mast cells, which are one of the primary targets of anti-histamines, have also been considered as pro-tumorigenic in mouse models of colon cancer ( 41 , 42 ). Since our study only covered patients that had been diagnosed before 2015, newer asthma medications that directly target the IL4/IL13/IL4R pathway such as dupilimab are not involved.…”

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

“…However, there are also studies in which MCs appear to play a protective role in CRC tumorigenesis (46)(47)(48). Notably, a recent work from Sakita and colleagues show that MCs could either promote or inhibit the development of colon tumors according to microenvironment stimuli, being tumorigenic in colitis-induced CRC and protective in murine models of sporadic CRC (49). This finding well fits with the current view that during CRC development MC activity may impact either in a beneficial or harmful fashion depending on the genetic background of mice and the specific tumor models (50).…”