| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Research Abstract |
Memory T cells are well known to be critically important for host defence in humans. Although they have been also suggested to play a significant role in tumor immunity, their clinical importance remains largely unknown. In this study, we tried to reveal the clinical significance of tumor-infiltrating CD45RO+memory T cells in several gastrointestinal malignancies. We performed immunohistochemistry on gastrointestinal cancer tissues including pancreatic, esophageal, and gastric cancer. Then we counted the cells stained positively for CD45RO+infiltrating into cancer tissue. As a result, CD45RO+hi patients had a significantly better postoperative prognosis than CD45RO+lo patients. Furthermore, the CD45RO status correlated with local immune activation. We found that tumor-infiltrating CD45RO+memory T cell has a significant independent prognostic value in human pancreatic cancer, and also our data suggested that adaptive immune response is functionally important in this fatal disease. Based
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on these clinical data, we extended our study to examine several novel strategies targeting T cell negative pathway including PD-1 and CTLA-4.In murine tumor models, anti-PD-1 and anti-CTLA-4 mAb had a significant antitumor effect on the prevention of liver metastasis and established tumors. Interestingly, the combination of PD-1 and CTLA-4 blockade displayed significant synergistic antitumor effect and resulted in complete inhibition in almost all mice. Further studies indicated that the combined treatment of PD-1/CTLA-4 blockade induced long-lasting and antigen-specific antitumor effect with resistance to tumor rechallenge. Furthermore, we also evaluated the importance of a recently identified T cell negative costimulator, B7-H3 expression. In human pancreatic cancer, B7-H3 expression was observed in almost all patients. Interestingly, anti-B7-H3 blocking mAb had also significant antitumor effect in vivo, similar to PD-1 and CTLA-4 blockade. A series of our studies provide new insights into targeting T cell negative pathway in tumor immunity and suggest that these promising strategies are potentially effective in human cancers. Less
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