The role of CD4+ FoxP3+ regulatory T cells (TREGS) in colorectal cancer (CRC) has continued to be unclear. TREGS act to suppress inflammatory mechanisms that are associated with tumor progression and can thus act to suppress the development of cancer. However, TREGS also function to inhibit anti-tumor T cell responses, thereby promoting cancer escape from immune surveillance. Many studies have been published on the frequencies of TREGS in the peripheral blood and tumors of CRC patients, but there is yet to be a consensus regarding the relationship between TREGS and disease outcome. In a report by Blatner et. al, the expression of RORγt in a subset of CD4+ FoxP3+ T cells was found to specifically mediate pathogenic pro-tumor activity compared with RORγt–CD4+FoxP3+ TREGS in CRC patients.
CD4+ FoxP3+ cells have been classified into three functional populations based on the expression of CD45RA and FoxP3: CD45RA+FoxP3int, CD45RA–FoxP3int, and CD45RA–FoxP3high. The CD45RA–FoxP3high population exhibits the most suppressive activity of these subsets. In the study by Blatner et. al, the CD45RA–FoxP3high population was found to be specifically expanded in peripheral blood mononuclear cells (PBMCs) and within the tumor of CRC patients and increased with cancer stage. Because IL-17 expressing CD4+ FoxP3+ cells have been described in the gut and enhanced in patients with CRC and Crohn’s disease, the authors examined CD4+ FoxP3+ populations for expression of the TH17 transcription factor, RORγt.
In CRC patients, a large fraction of all three subsets of TREGS in PBMCs and in the tumor were found to express RORγt. Interestingly, when TREG populations were sorted from healthy donors versus CRC patients, CRC patient TREGS retained suppressive activity over T cell proliferation but had lost their ability to suppress mast cell degranulation. Expression of IL-17 was also found in a large percentage of CRC TREGS, in a fashion mutually exclusive from IL-10 expression.
To further explore the role of RORγt in CRC, APC∆468 polyposis-prone mice were crossed with mice deficient in RORγt. RORγt-/-APC∆468 mice were highly resistant to polyp development, had reduced expansion of splenic proinflammatory macrophages, myeloid-derived suppressor cells (MDSCs) and polyp-associated mast cells, compared with RORγt+APC∆468 mice. Interestingly, the effect of RORγt deficiency in APC∆468 mice was not phenocopied by the loss of IL-17. Instead, although IL-17 deficiency reduced the frequency of polyps, mast cell recruitment to polyps was enhanced, and ultimately IL-17-/-APC∆468 mice developed invasive lesions.
Overall, this study revealed several fascinating points: CD4+FoxP3+RORγt+ cells appear to be a pathogenic TREG subset that have lost their anti-inflammatory properties and are specifically expanded in CRC patients where they assist in disease progression. The function of RORγt was not synonymous with IL-17 in TREGS, indicating that other effects of RORγt contribute to the role of these cells in tumor pathogenesis. Thus, the roles and relationships between FoxP3, RORγt, and IL-17 in TREGS deserve further attention in CRC pathogenesis. Hopefully, a clearer understanding of this newly identified subset of RORγt+ TREGS and their role in CRC progression will enable much improved methodology for targeting specific TREGS populations in CRC and other disease settings.
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