Abstract

<div>Abstract<p><b>Purpose:</b> Regulatory T cells (Treg) accumulate in tumor tissues and the peripheral blood of cancer patients and may persist after therapies. This cross-sectional study examines effects of adjuvant chemoradiotherapy (CRT) on Treg numbers and function in head and neck squamous cell carcinoma (HNSCC) patients.</p><p><b>Experimental Design:</b> The frequency and absolute numbers of CD4<sup>+</sup>, ATP-hydrolyzing CD4<sup>+</sup>CD39<sup>+</sup> and CD8<sup>+</sup> T cells, and expression levels of CD39, CD25, TGF-β–associated LAP and GARP on Treg were measured by flow cytometry in 40 healthy donors (NC) and 71 HNSCC patients [29 untreated with active disease (AD); 22 treated with surgery; 20 treated with CRT]. All treated subjects had no evident disease (NED) at the time of phlebotomy. In an additional cohort of 40 subjects with AD (<i>n</i> = 15), NED (<i>n</i> = 10), and NC (<i>n</i> = 15), <i>in vitro</i> sensitivity of CD4<sup>+</sup> T-cell subsets to cisplatin and activation-induced cell death (AICD) was tested in Annexin V–binding assays.</p><p><b>Results:</b> CRT decreased the frequency of circulating CD4<sup>+</sup> T cells (<i>P</i> < 0.002) but increased that of CD4<sup>+</sup>CD39<sup>+</sup> Treg (<i>P</i> ≤ 0.001) compared with untreated or surgery-only patients. Treg frequency remained elevated for >3 years. CRT increased surface expression of LAP, GARP, and CD39 on Treg. <i>In vitro</i> Treg were resistant to AICD or cisplatin but conventional CD4<sup>+</sup> T cells (T<sub>conv</sub>) were not. CRT-induced Treg from AD or NC subjects upregulated prosurvival proteins whereas T<sub>conv</sub> upregulated proapoptotic Bax.</p><p><b>Conclusions:</b> Highly suppressive, cisplatin-resistant Treg increase in frequency and persist after CRT and could be responsible for suppression of antitumor immune responses and recurrence in HNSCC. <i>Clin Cancer Res; 19(23); 6585–96. ©2013 AACR</i>.</p></div>

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