Colorectal cancer (CRC) is the second most commonly diagnosed cancer in women and the third in men in North America and Europe. CRC is associated with inflammatory responses in which intestinal pathology is caused by different cell populations including a T cell dysregulation that concludes in an imbalance between activated T (Tact) and regulatory T (Treg) cells. Treg cells are CD4+Foxp3+ cells that actively suppress pathological and physiological immune responses, contributing to the maintenance of immune homeostasis. A tumor-promoting function for Treg cells has been suggested in CRC, but the kinetics of Treg cells during CRC development are poorly known. Therefore, using a mouse model of colitis-associated colon cancer (CAC) induced by azoxymethane and dextran sodium sulfate, we observed the dynamic and differential kinetics of Treg cells in blood, spleen and mesenteric lymph nodes (MLNs) as CAC progresses, highlighting a significant reduction in Treg cells in blood and spleen during early CAC development, whereas increasing percentages of Treg cells were detected in late stages in MLNs. Interestingly, when Treg cells were decreased, Tact cells were increased and vice versa. Treg cells from late stages of CAC displayed an activated phenotype by expressing PD1, CD127 and Tim-3, suggesting an increased suppressive capacity. Suppression assays showed that T-CD4+ and T-CD8+ cells were suppressed more efficiently by MLN Treg cells from CAC animals. Finally, an antibody-mediated reduction in Treg cells during early CAC development resulted in a better prognostic value, because animals showed a reduction in tumor progression associated with an increased percentage of activated CD4+CD25+Foxp3- and CD8+CD25+ T cells in MLNs, suggesting that Treg cells suppress T cell activation at early steps during CAC development.
Colorectal Cancer (CAC) is the second most commonly diagnosed cancer in women and the third in men in North America and Europe. CAC is associated with inflammatory responses where intestinal pathology is caused by a T-cell dysregulation that concludes in an imbalance between T activated (Tact) and T regulatory (Treg) cells. Treg cells are CD4+Foxp3+ cells that actively suppress pathological and physiological immune responses, contributing to the maintenance of immune homeostasis. It has been suggested a tumor-promoting function for Treg cells in CAC, but the kinetics of Treg cells during CAC development is poorly known. Thereby we used a mouse model of CAC induced by azoxymethane and three cycles of dextran sodium sulfate (DSS, 2%). We analyzed the percentage of Treg cells in blood, spleen and mesenteric lymph nodes (MLN) in each cycle. A significant reduction of Treg cells in blood and spleen during the first cycle, but increased percentage of Treg cells during the second and third cycle was observed. We did not observe reduction on Treg cells in the first DSS cycle in MLN, but a significant increase in percentage was detected during the second and third cycle of DSS. A Higher percentage of Treg cells-expressing PD1, CD127 and Tim-3 during the second and third DSS cycle in spleen and MLN was observed, whereas CD25 had no changes. However, we found increasing percentages of CD4+CD25+Foxp3− Tact cells only in the first DSS cycle in blood, spleen, and MLN. These results suggest that a gradually increased number of Treg cells suppress Tact cells during the second and third DSS cycle. Depletion of Treg cells with anti-CD25 PC61 antibody in the second DSS cycle increased percentages of CD4+CD25+Foxp3− Tact and TCD8+ cells, with an impact in tumorigenesis.
STAT6 signaling pathway has important pathophysiologic implications in a variety of cell types and diseases. On cancer studies, mice lacking STAT6 display enhanced tumor immunity to both primary and metastatic mammary carcinomas. In humans, STAT6 protein has been found to be constitutively activated in several cancer types. However, the role of STAT6 in influencing the resistance or susceptibility of colon cancer cells to apoptosis and invasiveness/metastasis has not yet been validated during in vivo colitis-associated colon cancer (CAC).This study aims to identify the effects of STAT6 in tumorigenesis utilizing STAT6-KO mice in an experimental CAC model and evaluating changes in immune cell populations in the absence of this gene. CAC was induced in both STAT6-KO and WT mice by injection of 12.5 mg/kg AOM followed by three rounds of 2% DSS exposure to elicit colitis. On day 63 after CAC induction, mice were sacrificed. Colonic inflammation, proliferation and tumorigenesis were evaluated. Tumor numbers per mouse (0.8 versus 19.6; P=0.0001), and bowel weight (0.3 versus 0.6 g; P=0.05) were significantly decreased in STAT6-KO mice compared to WT mice. Furthermore, both inflammation and proliferation scores in colon from STAT6-KO mice were significantly lower than WT mice. Although additional studies are needed to clarify the mechanism(s) underlying improved anti-tumor immunity in STAT6-KO mice, these results may be a basis for an immunotherapy strategy in CAC development.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.