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.
Highlights
Regulatory CD4+ T cells (Treg) prevent tumor clearance by conventional T cells (Tconv) comprising a major obstacle of cancer immune-surveillance
To clarify whether in human cancers antigen-experienced tumor-antigen reactive effectors (Teff) or memory Tconv contribute to the Treg repertoire in vivo, we compared the T-cell receptor (TCR) repertoires of antigen-experienced TA-specific CD4+Teff clones and Treg in peripheral blood (PB) of breast cancer patients
We focused on CD4+Teff reactive to the tumor-associated antigen (TAA) MAMI, a 50 amino acidlong peptide derived from Mammaglobin, which is commonly overexpressed in breast tumors[34]
Summary
Regulatory CD4+ T cells (Treg) prevent tumor clearance by conventional T cells (Tconv) comprising a major obstacle of cancer immune-surveillance. Recognizing the tumor as self, Treg, tumor-infiltrating subsets, inhibit tumor eradication by tumor-antigen (TA)-reactive Teff[4] through classical suppressive mechanisms and exert direct nonimmune pro-tumorigenic effects through the production of molecules that support cancer development[5]. Among these are VEGF, which promotes enhanced tumor angiogenesis[6], AREG, which induces lung tumor growth[7], and RANKL, which drives lung metastasis of breast cancer[8]. While originally Treg development was only assigned to the thymus (natural Treg; nTreg), recent data demonstrate that Treg can be generated in the periphery (outside the thymus) from originally FOXP3− Tconv under suboptimal TCR stimulation conditions (peripherally induced Treg; pTreg or iTreg)[13,14,15]
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