Clinical significance and therapeutic potential of targeting B7-H3 in pancreatic cancer

1518 B7-H3, a new member of the B7 family, has been reported to provide both positive and negative signals to T cells under various physiological and pathological circumstances. To date, the precise role of B7-H3 in tumor immunity remains largely unknown. In this study, we investigated the expression of B7-H3 in human pancreatic cancer and therapeutic potential of targeting B7-H3 as a novel immunotherapy. First, we examined the expression of B7-H3 on 67 pancreatic cancer tissues by immunohistochemistry. Positive staining was seen both on the cell membrane and in the cytoplasm of cancer cells in almost all patients. Thus, data suggested that B7-H3 might be a critical regulator and potential target for immunotherapy against pancreatic cancer. Toward clinical application, we evaluated therapeutic efficacy of targeting B7-H3 in vivo. To this end, we utilized a murine pancreatic cancer cell line, PAN02, and employed a blocking anti-mouse B7-H3 mAb (MJ-18). By MTS assay, we did not see any direct effect of mAb on the tumor growth in vitro. Then, PAN02 was orthotopically implanted in the pancreas of the syngeneic C57BL/6 mice. On the next day of tumor implantation, anti-B7-H3 mAb treatment was started (0.3mg, three times a week for 3 weeks). The treatment induced substantial antitumor effect and significantly inhibited tumor growth compared to controls (tumor volume at 4 weeks; anti-B7-H3 mAb, n=10, 144.6±13.3 mm3, control, n=9, 320.4±36.1mm3, P=0.0002). Real-time PCR analysis further revealed that B7-H3 blockade promoted T cell infiltration and also downregulated VEGF in tumors, suggesting that B7-H3 blockade induce local immune activation and inhibit tumor angiogenesis, thereby resulting in tumor regression. Finally, we examined the efficacy of combination therapy of B7-H3 blockade and conventional chemotherapy. We used gemcitabine that is currently standard chemotherapeutic agent for pancreatic cancer. Gemcitabine treatment (0.8mg, every three days, 5 times) had a modest antitumor effect (n=5, 108.6±9.3 mm3, P=0.0011). Interestingly, B7-H3 blockade and gemcitabine exerted significant synergistic effect on pancreatic cancer, resulting in substantial response without overt toxicity (n=5, 27.1±4.9 mm3, P