Over-expression of fatty acid synthase (FAS) in sera and tissue in patients with pancreatic carcinoma

Proc Amer Assoc Cancer Res, Volume 47, 2006 413 PD-L/PD-1 pathway has been recently suggested to play a pivotal role in the immune evasion of tumors from host immune system. However, the clinical relevance of PD-L/PD-1 pathway on prognosis and characteristics of cancer patients has not been fully determined yet. In this study, we tried to reveal the clinical importance and therapeutic potential of PD-L/PD-1 pathway in pancreatic cancer that is one of most aggressive and intractable tumors. To this end, we examined PD-L1 and PD-L2 expression by RT-PCR in four human pancreatic cancer cell lines including PK-8, MiaPaca-2, Panc-1 and Capan-2. Both PD-L1 and PD-L2 were expressed in all cell lines. By immunohistochemical analysis using anti-human PD-L1 (MIH1) and anti-human PD-L2 (MIH18) mAb, we examined the expressions in 51 patients with pancreatic cancer who underwent surgery. PD-L1 and PD-L2 were stained mainly in the cytoplasm of pancreatic cancer cells. PD-L1 positive patients (n=20) had a significantly poorer prognosis than the negative patients (n=31) (P=0.023) (1-year survival rate, 35.6% vs 60.3%, 2-year survival 10.7% vs 32.8%, 3-year survival 10.7% vs 23.4%, respectively). There were no significant differences in prognosis between PD-L2 positive (n=14) and negative patients (n=37). In subgroup analysis, significant differences were noted in survival rate between positive and negative patients of PD-L1 when categorized by the following variables: T3 status (P=0.032, 1-year survival 44.9% vs 62.9%), N0 status (P=0.033, 1-year survival 25.0% vs 87.5%) and pathologic stage of IIA (P=0.010, 1-year survival 25% vs 100%). Furthermore, immunohistochemical analysis revealed that PD-L1 expression was inversely correlated with tumor-infiltrating T lymphocytes, more profoundly CD8+ T cells (CD4+ T cell P=0.026, CD8+ T cell P<0,001). These clinical data have suggested that PD-L1/PD-1 pathway may be a critical regulator in human pancreatic cancer. Then, to examine the therapeutic efficacy of targeting this pathway, we utilized a murine syngeneic model. PAN02 (a murine pancreatic cancer cell line) were subcutaneously inoculated into the lower flank region of syngeneic C57BL/6 mice. When a small palpable lump (around 3mm) was evident, anti-mouse PD-L1 mAb (MIH5) therapy was started. Anti-PD-L1 mAb of 0.3mg was intraperitoneally injected every other day for four weeks. Control mice received rat IgG. The treatment induced substantial antitumor effect in vivo and significantly inhibited tumor growth compared to control (tumor volume at 4 weeks; anti-PD-L1 mAb, 136 mm3, control, 332 mm3). Immunohistochemical analysis has revealed that PD-L1 blockade promoted CD8+ T cell infiltration into the established tumor. In conclusion, our data suggest for the first time that PD-L1 status may be a new predictor of prognosis for patients with pancreatic cancer and provide the rationale for developing a novel immunotherapy of targeting PD-1 pathway.