Early and Partial Reduction in CD4⁺Foxp3⁺ Regulatory T Cells during Colitis-Associated Colon Cancer Induces CD4⁺ and CD8⁺ T Cell Activation Inhibiting Tumorigenesis

Abstract

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.

Increase in CD4+FOXP3+ regulatory T cell number and upregulation of the HGF/c‑Met signaling pathway during the liver metastasis of colorectal cancer

“…The role and potential mechanism of CD4 + FOXP3 + Tregs have also been investigated in colitis-associated colon and colorectal cancer. Notably, Olguín et al (29) discovered that the percentage of CD4 + FOXP3 + Tregs was increased in colitis-associated colon cancer. Another study by Syed Khaja et al (17) revealed that numbers of CD4 + FOXP3 + Tregs were increased in colorectal cancer tissues.…”

The role of autophagy in colitis-associated colorectal cancer

“… 5 Tregs and Th17 cells have tumor-promoting functions during CAC formation, 6 , 7 whereas CD8 + T cells protect against CAC tumorigenesis. 8 In addition, cancer-associated fibroblasts (CAFs) promote the growth of colitis-associated neoplasms through activation of ERK signaling and increase colon cancer angiogenesis via IL-6 and VEGF signaling. 9 , 10 In addition to providing a survival advantage by inducing angiogenesis, tumor-associated vessels contribute to CAC tumorigenesis by facilitating pro-inflammatory leukocyte extravasation.…”

Autophagy is positively associated with the accumulation of myeloid‑derived suppressor cells in 4‑nitroquinoline‑1‑oxide‑induced oral cancer

“…The multiple subpopulations of Tregs are distinguished by the expression of different cell surface markers, including FoxP3, CD4, CD25 and CD127 ( 45 , 46 ). The present study examined the level of CD4 + Foxp3 + Tregs, which has been widely reported in previous studies ( 47 – 52 ). The multiple subpopulations of Tregs may play different roles in oral carcinogenesis and the authors hope to examine CD4 + CD25 + CD127 low FoxP3 + Tregs in future studies.…”