In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction

Abstract

T-regulatory cells (Treg) and mast cells (MC) are abundant in colorectal cancer (CRC) tumors. Interaction between the two is known to promote immune suppression or loss of Treg functions and autoimmunity. Here, we demonstrate that in both human CRC and murine polyposis the outcome of this interaction is the generation of potently immune suppressive but proinflammatory Treg (ΔTreg). These Treg shut down IL10, gain potential to express IL17, and switch from suppressing to promoting MC expansion and degranulation. This change is also brought about by direct coculture of MC and Treg, or culture of Treg in medium containing IL6 and IL2. IL6 deficiency in the bone marrow of mice susceptible to polyposis eliminated IL17 production by the polyp infiltrating Treg, but did not significantly affect the growth of polyps or the generation of proinflammatory Treg. IL6-deficient MC could generate proinflammatory Treg. Thus, MC induce Treg to switch function and escalate inflammation in CRC without losing T-cell–suppressive properties. IL6 and IL17 are not needed in this process.

Mast Cell 5-Lipoxygenase Activity Promotes Intestinal Polyposis in APCΔ468 Mice

“…In particular, we found that functional depletion of mast cells led to a regression of murine intestinal polyposis with decreased proliferative indices. We also showed that mast cells alter the tumor immune response (14). The immune system is believed to mediate the body's recognition and rejection of tumor cells.…”

“…We have previously reported finding elevated IL-17 in polyposis and suggested that polyposis is a Th17-driven disease (14,34). Both CD4þ T-cells and antigen presenting cells contribute to long-term Th17 inflammation.…”

Mast Cells: Potential Positive and Negative Roles in Tumor Biology

“…By generating polyp-prone (APC D468 ) chimeric mice bearing bone marrow derived from WT mice or mice deficient in genes important for mast cell development or trafficking, Gounaris and colleagues provided evidence suggesting that mast cells (and/or other bone marrow-derived cell types also influenced by these mutations) were essential hematopoietic components that favored the development of intestinal polyps (46). Using this mouse model, the same group investigated cross-talk between Tregs and mast cells and reported that mast cells can induce phenotypic changes in classical immunosuppressive and anti-inflammatory Tregs, causing them to become a "proinflammatory Treg" population that can promote tumor growth (47)(48)(49). Evidence of the importance of mast cells and tumor-derived SCF in the development of plexiform neurofibromas has been provided by Clapp and colleagues (20,50,51).…”

Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the primary off-target of tyrosine kinase inhibitors

“…Some of us (Gri et al, 2008;Piconese et al, 2009) and others (Lu et al, 2006) have demonstrated MC interaction with regulatory T cells (Treg), a well-known T cell subset endowed with immunosuppressive properties, in anaphylaxis, autoimmunity and transplantation tolerance. A bidirectional cross-talk is established between Treg and MCs in mouse colon polyps and human colorectal cancers, with Treg fostering mastocytosis and MCs promoting Treg skewing into IL-17-producing cells favoring inflammation and tumor growth (Gounaris et al, 2009;Blatner et al, 2010). Treg-MCs partnership recapitulates the complexity of innate-adaptive networks characterizing gut inflammation and represents a novel target for cancer immunotherapy (Colombo and Piconese, 2009).…”