B7-H1 Overexpression Regulates Epithelial–Mesenchymal Transition and Accelerates Carcinogenesis in Skin

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. Cancer Res; 71(4); 1235-43. Ó2010 AACR.

Lung Cancer-derived Galectin-1 Enhances Tumorigenic Potentiation of Tumor-associated Dendritic Cells by Expressing Heparin-binding EGF-like Growth Factor

“…Tumor cells consistently release immunosuppressive and proinflammatory factors that facilitate tumor immune-escape and tumor progression (20,21). In contrast, tumor-surrounding cells, such as dendritic cells, also secrete certain factors to modulate the development of cancer (22).…”

B7-H1 Expression Model for Immune Evasion in Human Papillomavirus-Related Oropharyngeal Squamous Cell Carcinoma

“…Cytotoxic T-lymphocytes become anergic when their PD-1 receptor is bound to B7-H1, hence silencing immune surveillance. Expression of B7-H1 in the tumor microenvironment enables the tumor cell to evade the immune system by causing either cytotoxic T-lymphocyte apoptosis or tumor cell resistance to lysis [17][18][19][20][21]. Increased cell surface expression of B7-H1 has been demonstrated in chronic infection and carcinomas [19,20,[22][23][24][25][26].…”

“…Increased cell surface expression of B7-H1 has been demonstrated in chronic infection and carcinomas [19,20,[22][23][24][25][26]. Studies have demonstrated immune evasion via B7-H1 expression to be associated with metastasis and poor prognosis in many different carcinomas, such as those arising in the kidney, skin, lung, and pancreas [21][22][23][24][25][26][27][28][29]. Effective blockade of PD-1 has shown to reverse T-cell anergy and improve outcomes [19,20].…”

Change in PD-L1 Expression After Acquiring Resistance to Gefitinib in EGFR-Mutant Non–Small-Cell Lung Cancer

“…38 Chen et al reported that EMT and PD-L1 expression are controlled by miR-200/ZEB1 in lung cancer cells. 39 We could not further studied PD-L1 expression in association with mesenchymal markers in tumor tissues due to the lack of available tumor specimen.…”