Intratumoral regulatory T cells upregulate immunosuppressive molecules in head and neck cancer patients

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Abstract
Although regulatory T cells (Treg) are highly enriched in human tumours compared with peripheral blood, expression of the immune-checkpoint receptors, immunosuppressive molecules and function of Treg in these two sites remains undefined. Tumour-infiltrating lymphocytes and peripheral blood lymphocytes were isolated from a cohort of head and neck squamous cell carcinoma (HNSCC) patients. The immunosuppressive phenotypes and function of intratumoral Treg were compared with those of peripheral blood Treg. The frequency of immune-checkpoint receptor-positive cells was higher on intratumoral FOXP3+CD25hi Treg compared with circulating Treg (CTLA-4, P=0.002; TIM-3, P=0.002 and PD-1, P=0.002). Immunosuppressive effector molecules, LAP and ectonucleotidase CD39 were also upregulated on intratumoral FOXP3+ Treg (P=0.002 and P=0.004, respectively). CTLA-4 and CD39 were co-expressed on the majority of intratumoral FOXP3+CD4+ Treg, suggesting that these molecules have a key role in regulatory functions of these cells in situ. Notably, intratumoral Treg exhibited more potently immunosuppressive activity than circulating Treg. These results indicate that intratumoral Treg are more immunosuppressive than circulating Treg and CTLA-4 and CD39 expressed can be potential target molecules to inhibit suppressive activities of intratumoral Treg in situ.

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