Transcriptional similarities of non-lymphoid tissue regulatory T cells in health, acute inflammation and cancer

Abstract

Regulatory T cells (Treg) are an anti-inflammatory, immune-regulatory T cell type. Besides their classical function in immune regulation, a highly activated subset of Treg cells can also migrate into tissues and promote homeostasis as well as regeneration. This non lymphoid tissue subset is characterized by the expression of tissue-specific marker genes and their highly regenerative and suppressive function. Previous research had highlighted the importance of tissue-specific Treg cells in regeneration upon organ damage and inflammation, but less is known in the context of tumor progression. In this study we therefore aimed to characterize murine Treg cells from three different tumor types (colorectal carcinoma, B16-F10 melanoma, MC38 adenocarcinoma) by their gene expression pattern and asses their clonal expansion via single cell RNA/TCR-sequencing. Under steady-state conditions, Treg cells across different tissues exhibit a shared molecular program with only a few tissue-specific genes. Our studies did not identify a uniform tumor-specific phenotype across all investigated tumor models. Instead, our findings emphasize the dynamic and adaptable nature of Treg cells, revealing tissue- and tumor-type-specific variations in their clonal sharing, expansion, cell interaction and recruitment patterns. Notably, these results suggest a potential role for the SLE as a priming environment for tumor-associated Tregs, with temporal dependencies in their migration and induction patterns differing between melanoma and colorectal tumor models. These insights provide a foundation for further research into antigen specificity, migration signals, and potential therapeutic targets. Finally, we identified genes that are specifically upregulated in the tumor context and thus indicate specific programs active in tumor-associated Treg cells, but absent in healthy non-lymphoid tissue Treg cells. These findings suggest potential targets or prognostic markers for Treg cell-specific immunotherapies and give valuable insights in the migration capacity of Treg cells in the context of cancer.