CD276 expression enables squamous cell carcinoma stem cells to evade immune surveillance

Immunosurveillance is a critical mechanism guarding against tumor development and progression. Checkpoint inhibitors have shown significant success in cancer treatment, but expression of key factors such as PD-L1 in putative cancer stem cell (CSC) populations in squamous cell carcinoma has been inconclusive, suggesting that CSCs may have developed other mechanisms to escape immune surveillance. Here we show that CSCs upregulate the immune checkpoint molecule CD276 (B7-H3) to evade host immune responses. CD276 is highly expressed by CSCs in mouse and human head and neck squamous cell carcinoma (HNSCC) and can be used to prospectively isolate tumorigenic CSCs. Anti-CD276 antibodies eliminate CSCs in a CD8+ T cell-dependent manner, inhibiting tumor growth and lymph node metastases in a mouse HNSCC model. Single-cell RNA sequencing (RNA-seq) showed that CD276 blockade remodels SCC heterogeneity and reduces epithelial-mesenchymal transition. These results show that CSCs utilize CD276 for immune escape and suggest that targeting CD276 may reduce CSCs in HNSCC. [Display omitted] •CSCs use CD276 to evade immune surveillance in SCC initiation and metastasis•CD276 is a functional cell surface marker to isolate CSCs from SCC•CD276 blockade remodels SCC heterogeneity with decrease of pEMT•CD276 blockade kills CSCs in a CD8+ T cell-dependent manner Wang et al. show that cancer stem cells (CSCs) utilize the immune checkpoint molecule CD276 (B7-H3) to evade immune surveillance during HNSCC initiation, development, and metastasis. CD276 blockade eliminates CSCs and inhibits tumor growth and metastasis by increasing anti-tumor immunity.