Single-cell RNA sequencing reveals a novel cell type and immunotherapeutic targets in papillary thyroid cancer

<jats:title>Abstract</jats:title><jats:p>Papillary thyroid cancer (PTC) is the most common thyroid malignancy. Although PTC usually has a favorable prognosis, some aggressive PTC subtypes and lymph node (LN) metastasis contribute to high rates of recurrence and poor clinical outcomes. We analyzed single-cell RNA sequencing (scRNA-seq) data from 15 samples, including primary tumors of PTC, metastatic LNs, and paracancerous tissues. After quality filtering, 28,205 cells were detected. Of these, 13,390 cells originated from 7 tumor tissues, 2,869 cells from 2 metastatic LNs, and 11,945 cells from 6 paracancerous tissues. The increase in the proportion of CD4<jats:sup>+</jats:sup> Tregs may be a key factor responsible for the immunosuppressive property of PTC. A novel cell type was identified, named Protective EGR1<jats:sup>+</jats:sup>CD4<jats:sup>+</jats:sup> T cell, which might be antagonistic to the CD4<jats:sup>+</jats:sup> Tregs and inhibit the formation of the immunosuppressive microenvironment and tumor immune evasion. Inhibitory checkpoints TIGIT and CD96 were found to be better targets than PD-1 for immune therapy in PTC patients with LN metastasis. For PTC patients without LN metastasis, however, PD-1, TIGIT, and CD96 could be suitable targets of immunotherapy. These findings would contribute to the further understanding of molecular mechanisms resulting in occurrence and development of PTC, and provide a theoretical rationale for targeted therapy and immunotherapy.</jats:p>