Non-small Cell Lung Cancer Induces an Immunosuppressive Phenotype of Dendritic Cells in Tumor Microenvironment by Upregulating B7-H3.

摘要

INTRODUCTION: : Tumors may shift the phenotype and function of dendritic cells (DC) toward the induction of tolerance. In the status of full maturity, DC express a multitude of T cell costimulatory molecules enabling them to induce immune reactions, whereas nonactivated resident DC lack these T cell stimulating capacities. Therefore, we investigated the changes in DC phenotype and expression of B7-H molecules induced by non-small cell lung cancer (NSCLC). METHODS: : The expression of T cell coinhibitory B7 molecules (B7-DC, B7-1, B7-2, B7-H1, B7-H3) on DC isolated from malignant and nonmalignant lung and lymph node tissue from patients attending curative surgery for NSCLC (n = 12) was analyzed. T cell stimulatory functions of DC isolated from malignant and nonmalignant lung and lymph node tissue samples were measured by allogeneic mixed lymphocyte reactions. Furthermore, the secretion of IL-10 and IL-12p40 by DC was analyzed (enzyme-linked immunosorbent assay). RESULTS: : B7-H3 was significantly upregulated in tumor-residing DC, whereas the expression of other B7 molecules, such as B7-DC, B7-1, B7-2, B7-H1, remained unchanged. Significantly reduced levels of T cell proliferation in mixed lymphocyte reactions with tumor-derived DC were recorded. Moreover, elevated concentrations of IL-10 were measured in tumor-derived DC, whereas IL-12 levels were reduced. CONCLUSION: : Our data indicate that (1) DC derived from NSCLC are immunosuppressive, and (2) under tumor conditions the coinhibitory molecule B7-H3 plays a crucial role in mediating the T cell suppressive effects of DC.