Regulatory T Cells Exhibit Distinct Features in Human Breast Cancer

Abstract

Summary Regulatory T (Treg) cells reside in lymphoid organs and barrier tissues where they control different types of inflammatory responses. Treg cells are also found in human cancers, and studies in animal models suggest that they contribute to cancer progression. However, properties of human intratumoral Treg cells and those present in corresponding normal tissue remain largely unknown. Here, we analyzed features of Treg cells in untreated human breast carcinomas, normal mammary gland, and peripheral blood. Tumor-resident Treg cells were potently suppressive and their gene expression pattern resembled that of normal breast tissue, but not of activated peripheral blood Treg cells. Nevertheless, a number of cytokine and chemokine receptor genes, most notably CCR8, were upregulated in tumor-resident Treg cells in comparison to normal tissue resident ones. Our studies suggest that targeting CCR8 for the depletion of tumor-resident Treg cells may represent a promising immunotherapeutic approach for the treatment of breast cancer.

Human lung tumor FOXP+ Tregs upregulate four “Treg-locking” transcription factors

“…Use of adjacent tumorfree tissue allows identification of tumor-specific, rather than tissue-specific, differences in Tregs and T cells, as discussed previously (34)(35)(36). In addition to showing increased numbers of Tregs in tumors compared with adjacent lung tissue, our study is the first to our knowledge to show tumor-specific increases in Treg numbers within lung LNs, even in early stages, when LNs are free of metastases.…”

“…Moreover, we found a negative correlation between Ki67 + expression in Tregs and tumor size, suggesting that along with tumor growth, factors such as hypoxia, nutrient deprivation, and tumor necrosis may impair division of immune cells, including Tregs. A recent study of Tregs in human breast cancer came to a similar conclusion by showing that the TCR repertoires between normal tissue and tumor-associated Tregs did not overlap, suggesting that Tregs are recruited (36).…”

Effector and Regulatory CD4+ T helper lineages in cancer

“…The classical ligand for CCR8 are CCL1 and CCL18, however it has been shown that CCL17 also induces migration of CCR8-expressing cells 44 , which is relevant in the cancer field as CCL17 has been strongly associated with tumour progression 27 . Same year, two independent research groups also described CCR8 as one of the main chemokine receptor in Tregs present in breast 45 , colorectal and non-small-cell lung cancer 46 . Whereas Plitas et al, mentioned that tumour environment has the ability to potentiate CCR8 expression in Tregs, De Simone et al, discussed that the presence of CCL18 in different tumours might be associated with the migration of CCR8 + cells 45,46 .…”

“…Same year, two independent research groups also described CCR8 as one of the main chemokine receptor in Tregs present in breast 45 , colorectal and non-small-cell lung cancer 46 . Whereas Plitas et al, mentioned that tumour environment has the ability to potentiate CCR8 expression in Tregs, De Simone et al, discussed that the presence of CCL18 in different tumours might be associated with the migration of CCR8 + cells 45,46 . In 2017, our research group characterized the presence of Th1, Th2, Th17 and Th1/17 Tregs in peripheral blood and several tissues, such as skin, colon, thymus, spleen and liver perfusates 31 .…”

“…Another possible explanation is the specific expansion of Th2-like subsets at the cancer site to reduce the antitumour immunological response. For example, the expression of TIGIT (T-Cell Immunoreceptor With Ig And ITIM Domains) has been found in tumour-infiltrating conventional CD4 + T-cells compared to circulating CD4 + Tcells 45 . It has been demonstrated that TIGIT contributes to the induction of a selective Treg-cell-mediated suppression of pro-inflammatory Th1 and Th17 cells but not Th2 cell responses 47 , thus it is possible that Th2 cells are not only recruited to the tumour site, but also promoted by evading TIGIT-mediated inhibition.…”