Abstract
B7-H1 (CD274) is a T-cell coinhibitory molecule that is also often induced on human carcinoma cells, where its expression has been implicated in immune escape. Under inflammatory conditions, B7-H1 is also inducible in normal epithelial cells but little is known about its involvement in conversion of normal cells to tumor cells. Here, we show that skin-specific expression of B7-H1 accelerates inflammatory carcinogenesis in a methylcholantrene (MCA)-induced model of squamous cell carcinoma (SCC). Inflammatory responses induced by MCA or phorbol ester TPA were clearly inhibited in B7-H1 transgenic mice (B7-H1tg mice). Antibody-mediated blockade of either B7-H1 or the related molecule PD-1 revealed that their ability to limit inflammation relied on ligand interactions made by B7-H1 or PD-1. Skin keratinocytes derived from B7-H1tg mice exhibited constitutive reduction of E-cadherin, and SCC induced in B7-H1tg mice also showed loss of E-cadherin along with elevated expression of the transcription factors Slug and Twist that drive epithelial-mesenchymal transition (EMT). Our results indicate that upregulation of B7-H1 in skin epithelial cells promotes EMT and accelerates carcinogenesis, revealing insights into the significance of B7-H1 overexpression on solid tumor cells and hinting at a close relationship between EMT and immune escape signaling pathways in cancer.
Highlights
B7-H1 (CD274) is one of the ligands for the coinhibitory receptor PD-1 (CD279), and the B7-H1:PD-1 pathway is involved in the induction and maintenance of peripheral tolerance [1, 2]
To investigate the role of B7-H1 in skin tumor formation, we used an intradermal injection of MCA to generate squamous cell carcinoma (SCC)
To address why B7-H1-overexpression in KCs induced higher tumor formation, we focused on molecules involved in the epithelial–mesenchymal transition (EMT; ref. 28, 29)
Summary
B7-H1 (CD274) is one of the ligands for the coinhibitory receptor PD-1 (CD279), and the B7-H1:PD-1 pathway is involved in the induction and maintenance of peripheral tolerance [1, 2]. B7-H1 is widely distributed on leukocytes and nonhematopoietic cells in lymphoid and nonlymphoid tissues. Nonlymphoid tissue-associated B7-H1 is found on pancreatic islets [3], keratinocytes 4), smooth muscle cells [5], and placenta [6] at inflammatory disease sites. IFN-g is a key cytokine in the induction of B7-H1.
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