STAT6 Is Critical for the Induction of Regulatory T Cells In Vivo Controlling the Initial Steps of Colitis-Associated Cancer

Abstract

Inflammation is the main driver of the tumor initiation and progression in colitis-associated colorectal cancer (CAC). Recent findings have indicated that the signal transducer and activator of transcription 6 (STAT6) plays a fundamental role in the early stages of CAC, and STAT6 knockout (STAT6−/−) mice are highly resistant to CAC development. Regulatory T (Treg) cells play a major role in coordinating immunomodulation in cancer; however, the role of STAT6 in the induction and function of Treg cells is poorly understood. To clarify the contribution of STAT6 to CAC, STAT6−/− and wild type (WT) mice were subjected to an AOM/DSS regimen, and the frequency of peripheral and local Treg cells was determined during the progression of CAC. When STAT6 was lacking, a remarkable reduction in tumor growth was observed, which was associated with decreased inflammation and an increased number of CD4+CD25+Foxp3+ cells in the colon, circulation, and spleen, including an over-expression of TGF-beta, IL-10, and Foxp3, compared to WT mice, during the early stages of CAC development. Conversely, WT mice showed an inverse frequency of Treg cells compared with STAT6−/− mice, which was followed by intestinal tumor formation. Increased mucosal inflammation, histological damage, and tumorigenesis were restored to levels observed in WT mice when an early inhibition/depletion of Treg cells was performed in STAT6−/− mice. Thus, with STAT6 deficiency, an increased number of Treg cells induce resistance against tumorigenesis, arresting tumor-promoting inflammation. We reported a direct role of STAT6 in the induction and function of Treg cells during CAC development and suggest that STAT6 is a potential target for the modulation of immune response in colitis and CAC.

The effects of the probiotic cocktail on modulation of the NF-kB and JAK/STAT signaling pathways involved in the inflammatory response in bowel disease model

“…Therefore, all these variations helped improve the inflammation, in line with other studies. Also, other investigators showed that increased STAT6 could play a significant role in colitis by affecting the IL-13 production [ 23 ], whereas a decrease in STAT6 could prevent apoptosis and disruption of cell membrane integrity [ 24 ].…”

IL-4 prevents adenosine-mediated immunoregulation by inhibiting CD39 expression

“…In our polyclonal activation assay, stimulation of total T cells under TH0 conditions in the absence of exogenous IL-4 induced phosphorylation of STAT6, likely due to the activation of infrequent IL-4–producing cells. Elevated pSTAT6 during T cell activation under nonpolarizing conditions has been shown to play an important role in T cell differentiation, such as the downregulation of TCF1 ( 30 ) and maintaining IRF4 ( 28 ) and FOXP3 ( 40 , 41 ) expression. Our experiments in the LCMV infection model showed that STAT6 inhibition upregulated the expression of CD39 on LCMV-specific SMARTA cells, providing additional evidence that the IL-4-STAT6-GATA3 pathway is activated and relevant in antiviral responses in vivo.…”

STAT6 controls the stability and suppressive function of regulatory T cells

“…Signal transducer and activator of transcription 6 (STAT6) participates in the cellular response to IL‐4 and IL‐13, which generate CD4+ Th2 cells. Our previous studies have demonstrated that STAT6 is an essential regulator of Tregs’ function during colitis‐associated colorectal cancer (CAC) [8]. STAT6 knockout (STAT6‐/‐) mice are highly resistant to CAC development and present a high number of CD4+Foxp3+CD25+ cells in the colon, circulation, and spleen, including over‐expressions of TGF‐β, IL‐10, and Foxp3, compared with wild‐type (WT) mice, during the early stages of CAC development [8].…”

“…Our previous studies have demonstrated that STAT6 is an essential regulator of Tregs' function during colitis-associated colorectal cancer (CAC) [8]. STAT6 knockout (STAT6-/-) mice are highly resistant to CAC development and present a high number of CD4+Foxp3+CD25+ cells in the colon, circulation, and spleen, including over-expressions of TGF-β, IL-10, and Foxp3, compared with wild-type (WT) mice, during the early stages of CAC development [8]. The increased frequency of Tregs during STAT6 deficiency coincided with minor intestinal damage, decreased cell proliferation in the early stages of injuryinduced tumor formation, and increased apoptosis in advanced tumors [8,9].…”

“…We detected an inverse Tregs frequency between WT and STAT6‐/‐ mice as CAC progressed. At an early stage of CAC induction, STAT6−/− mice had twice the number of CD4+Foxp3+CD25+ Tregs in the circulation and the spleen compared with WT [8], suggesting that Tregs expansion is negatively controlled by a STAT6‐ dependent mechanism, which probably limits the number of Tregs at sites of inflammation. However, whether STAT6 is involved in the process of Foxp3 expression, and Tregs’ stability and suppressive function remains unclear.…”