Plac1 ⁺ Tumor Cell‐Treg Interplay Supports Tumorigenesis and Progression of Head and Neck Cancer

Cancer/testis antigen (CTA) family is restricted to germline and tumor cells and plays an important role during cancer initiation and progression. Five single-cell and two bulk RNA-seq datasets are integrated to screen genes in the CTAs family, revealing that Placenta specific protein 1 (Plac1) is specifically expressed in head and neck squamous cell carcinoma (HNSCC) cells. Sp1 Transcription (SP1) is identified as a specific regulator of Plac1, which is confirmed by cleavage under targets and tagmentation (CUT&Tag)-seq. With in vitro experiments, in vivo subcutaneous tumor, and a transgenic autochthonous tumor model, it is revealed that Plac1 expression promotes HNSCC progression by inducing epidermal growth factor receptor endocytosis and recycling to increase PI3K/AKT signaling pathway activity. Then, it is revealed that Plac1⁺ tumor cells recruit CD4⁺ T cells via CXCL11/CXCR3 and induce Treg differentiation via PVR/TIGIT, which in turn activates the tumorigenic signaling of Plac1⁺ tumor cells via LTA/LTBR and forms a reciprocal protumor loop. These findings provide insights into molecular features of CTAs in HNSCC and facilitate the development of personalized treatment strategies.