Author:

Keywords:

Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, SINGLE CELLS, BONE-MARROW, RNA-SEQ, RECEPTOR, EXPRESSION, FOXP3, REPERTOIRE, EFFECTOR, SUBSETS, METHYLATION, Antigens, Neoplasm, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Clone Cells, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Lymphocyte Activation, Neoplasm Staging, Receptors, Antigen, T-Cell, Single-Cell Analysis, T-Lymphocytes, Regulatory, Th1 Cells, Transcriptome, C14/18/092#54689607

Abstract:

Regulatory CD4+ T cells (Treg) prevent tumor clearance by conventional T cells (Tconv) comprising a major obstacle of cancer immune-surveillance. Hitherto, the mechanisms of Treg repertoire formation in human cancers remain largely unclear. Here, we analyze Treg clonal origin in breast cancer patients using T-Cell Receptor and single-cell transcriptome sequencing. While Treg in peripheral blood and breast tumors are clonally distinct, Tconv clones, including tumor-antigen reactive effectors (Teff), are detected in both compartments. Tumor-infiltrating CD4+ cells accumulate into distinct transcriptome clusters, including early activated Tconv, uncommitted Teff, Th1 Teff, suppressive Treg and pro-tumorigenic Treg. Trajectory analysis suggests early activated Tconv differentiation either into Th1 Teff or into suppressive and pro-tumorigenic Treg. Importantly, Tconv, activated Tconv and Treg share highly-expanded clones contributing up to 65% of intratumoral Treg. Here we show that Treg in human breast cancer may considerably stem from antigen-experienced Tconv converting into secondary induced Treg through intratumoral activation.