Clinical importance and therapeutic potential of targeting PD-L/PD-1 pathway in pancreatic cancer
Presentation Start/End Time:
Abstract Number: 4129
Tuesday, Apr 17, 2007, 10:25 AM -10:40 AM
Location:
Room 409 A-B, Los Angeles Convention Center
Author Block:
Takeo Nomi , Masayuki Sho , Takahiro Akahori , Kaoru Hamada , Hiromichi Kanehiro , Hideo Yagita , Miyuki Azuma , Yoshiyuki Nakajima . Department of Surgery,Nara Medical University, Nara, Japan, Second Department of Internal Medicine, Nara Medical University, Nara, Japan, Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan, Department of Molecular Immunology, Graduate School,Tokyo Medical and Dental University, Tokyo, Japan
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 has not been fully elucidated yet. In this study, we tried to reveal the clinical importance of PD-L expression in human pancreatic cancer and therapeutic potential of PD-L/PD-1 pathway toward developing novel immunotherapy. First, we examined the expressions of PD-L1 and PD-L2 in 51 patients with pancreatic cancer who underwent surgery by immunohistochemical analysis.
As a result, PD-L1-positive patients had a significantly poorer prognosis than the negative patients (P=0.016), while there were no significant differences in prognosis between PD-L2-positive and negative patients. 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=0.019), N0 status (P=0.019), and pathological stage of IIA (P=0.006). Furthermore, we found that PD-L1 expression was inversely correlated with tumor-infiltrating T lymphocytes, more profoundly CD8+ T cells (CD4+ T cell P=0.019, CD8+ T cell P<0.0001).
These clinical data have suggested that PD-L1/PD-1 pathway may be functionally important in human pancreatic cancer. Then, we explored the therapeutic potential of targeting this pathway toward clinical application. PAN02, 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 tumor growth compared to controls. Real-time PCR analysis revealed that PD-L1 blockade promoted CD8+ T cell infiltration. This was also confirmed by immunohistochemistry. In addition, the expressions of IFN-gamma, perforin, and granzyme B were significantly upregulated in tumors treated with anti-PD-L1 mAb compared to controls (P=0.030, 0.012, and 0.015, respectively). Data suggested that PD-L1 blockade promoted CD8+ T cell infiltration into established pancreatic cancer, thereby resulting in induction of local immune activation.
Finally, we examined the efficacy of combination therapy of PD-L1 blockade and conventional chemotherapy. To this end, we employed gemcitabine that is currently standard chemotherapeutic agent for pancreatic cancer. Interestingly, PD-L1 blockade and gemcitabine exerted significant synergistic effect on pancreatic cancer, resulting in complete response without overt toxicity. In conclusion, our data demonstrate for the first time that PD-L1/PD-1 pathway may play a critical role in human pancreatic cancer and provide the rationale for developing a novel immunotherapy of targeting this pathway against this fatal disease. |
