Altered regulatory T cells: A consequence of mast cells in colorectal cancer

I justed came across this paper by Blatner et al. Colorectal cancer is characterised by abundant Tregs and mast cells. However, mechanisms on how the tumor is able to survive in spite of such atmosphere is unclear. Here the authors study human CRC and murine polyposis tumors. The authors report systemic skewing of Treg from anti- to proinflammatory functions in both human CRC and murine polyposis; which they call "altered Tregs". MC are target of suppression by Treg but at the same time play a critical role to reverse the anti-inflammatory function of the Treg. They predict that targeting the pathogenic cross-talk between Treg and MC to allow recovery of Treg antiinflammatory functions will help to control CRC.
First, the  authors show that cytokine milieu in the tumors show increased IL17, TGFβ, IL6, and IL1β with corresponding reductions in IL10 and INFγ; these favor Th17 polarization.They then show that there is increased FoxP3 Tregs and mast cells in the colorectal cancer tumors. These tregs from patient tumors are unable to suppress mast cell degranulation, lack IL10 but show increased IL17 when compared to healthy donors. Then, the authors show that IL6 enables the diversion of healthy human Tregs to a pro-inflammatory phenotype with ability to inhibit CD4 T cells. The authors even generate pSTAT3+ rpo-inflammatory Tregs by co-culturing of naive Treg with primary MC. However, by performing bone marrow transplantation experiments, the authors show that IL6 is sufficient but not absolutely necessary for Treg conversion.Thus, MC induce Treg to switch function and escalate inflammation in CRC without losing T-cell–suppressive properties without the need of  IL6 and IL17 in this process.


Suggested Reading:
1. Blatner et al, In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction, PNAS 2010,  107 (14), 6430-6435 
2. Gri G, et al. CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction. Immunity 2008, 29:771–781. 
3. Piconese S, et al. Mast cells counteract regulatory T cell suppression through interleukin-6 and OX40/OX40L axis toward Th17 cell differentiation. Blood 2009, 114:2639–2648.