2006 Fiscal Year Final Research Report Summary
A NOVEL THERAPY OF TARGETING INTRATUMORAL INTERSTITIAL TISSUE IN PANCREATIC CANCER
| Project/Area Number |
16591343
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Nara Medical University |
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Principal Investigator |
SHO Masayuki NARA MEDICAL UNIVERSITY, DEPARTMENT OF SURGERY, ASSISTANTPROFESSOR, 医学部, 講師 (50364063)
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| Project Period (FY) |
2004 – 2006
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| Keywords | PANCREATIC CANCER / ANTIBODY THERAPY / INTERSTITIAL TISSUE |
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| Research Abstract |
We examined the expressions of PD-Ll and PD-L2 in pancreatic cancer by immunohistochemical analysis. As a result, PD-L1-positive patients had a significantly poorer prognosis than the negative patients, while there were no significant differences in prognosis between PD-L2-positive and negative patients. Furthermore, we found that PD-Ll expression was inversely correlated with tumor-infiltrating T lymphocytes, more profoundly CD8+ T cells. These clinical data have suggested that PD-Ll/PD-1 pathway may be functionally important in human pancreatic cancer. Then, we explored the therapeutic potential of targeting this pathway toward clinical application. PANO2, a murine pancreatic cancer cell line, was subcutaneously inoculated into the syngeneic C57BL/6 mice. When tumor became around 3mm in size, anti-mouse blocking PD-L1 (MIH-5) or PD-1 (RMP1-14) mAb treatment was started (0.3mg, every other day for 4 weeks). The treatment induced substantial antitumor effect and significantly inhibited
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tumor growth compared to controls. Finally, we examined the efficacy of combination therapy of PD-L1 blockade and conventional chemotherapy. PD-Ll blockade and gemcitabine exerted significant synergistic effect on pancreatic cancer, resulting in complete response without overt toxicity.
Next, we also tried to clarify the importance of TWEAK/Fn14 pathway in human pancreatic cancer. First, we examined the expression of TWEAK and Fn14 in human pancreatic cancer tissues. We performed immunohistochemical analysis on these samples using anti-human TWEAK mAb and anti-human Fn14 mAb. As a result, positive staining for TWEAK was detected in 15 (29%) and positive for Fn14 was detected in 31 (61%). These data suggested that TWEAK and Fn14 might play some role in human pancreatic cancer. Finally, we examined the antitumor effect of TWEAK and Fn14 mAb on tumor growth in vitro. Coculture with anti-TWEAK mAb induced 47-53% cell growth inhibition compared to control Ig. Similarly, coculture with anti-Fn14 mAb induced 34-52% inhibition. Taken together, TWEAK/Fn14 pathway may be functional and important in pancreatic cancer. Less
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