Characterization of CCR8+ regulatory T cells in human tumors and healthy tissue
Loading...
Date issued
Authors
Editors
Journal Title
Journal ISSN
Volume Title
Publisher
Reuse License
Abstract
Regulatory T (Treg) cells are well known for their immune-regulatory functions, namely restraining excessive inflammation and mediating peripheral tolerance to self- antigens, for which they rely on the transcription factor FOXP3. A highly-activated, effector-like subset of Treg cells can also be found in non-lymphoid tissues. In addition to the immunosuppressive program, this subset further has tissue regenerative properties and is characterized by the expression of the transcription factor BATF and the surface receptor CCR8.
While pivotal for maintaining tissue homeostasis, the tissue-regenerative function of Treg cells could be deleterious in the context of cancer. It is still unclear, whether this tissue-specific CCR8+ Treg cell subset can also be found in the tumor microenvironment. In the literature, Treg cells found in tumors, often referred to as “tumor Treg” cells, are described to have a similar phenotype to CCR8+ Treg cells, and efforts are put into therapeutically targeting this cell type. One drawback of the majority of these studies, however, is that Treg cells isolated from the tumor are compared to Treg cells isolated from peripheral blood. This does not allow for the deconvolution of tumor-vs-healthy and lymphoid-vs-non-lymphoid differences.
In this study, we performed a molecular characterization with single-cell resolution of human T cells from a variety of healthy tissues, inflamed tissue, and tumors, with the aim of comparing CCR8+ Treg cells from the tumor to their non-lymphoid tissue counterparts as well as other cell types in the tissues. We analyzed chromatin accessibility genome-wide (via single-cell ATAC sequencing) to infer transcriptional programs, as well as gene expression profiles, using single-cell RNA sequencing. Our investigation reveals shared molecular programs in human CCR8+ Treg cells, irrespective of (non-lymphoid) tissue type or disease state (healthy, inflamed, primary tumor, and metastasis). Moreover, CCR8+ Treg cells from tumor did not show significant differences from CCR8+ Treg cells from healthy tissue at the transcriptional level. T cell receptor (TCR) analysis of CCR8+ Treg cells from the tumor and healthy tissue revealed shared clones between the disease states, identifying a clonal relationship.
Taken together, our results argue against a special “tumor Treg” cell subset, but rather suggest a common CCR8+ Treg cell type common to the tumor and healthy tissue. This finding calls for caution regarding the development of “tumor Treg” cell- targeting therapies, since the presence of CCR8+ Treg cells in healthy tissue, essential for peripheral tolerance and tissue homeostasis, suggests potential unintended consequences of such interventions.