Induction of powerful secondary immune response by blocking T cell negative pathway prior to surgery
Abstract Number: 3803
Author Block:
Takahiro Akahori, Masayuki Sho, Takeo Nomi, Ichiro Yamato, Shinji Nakamura, Koji Enomoto, Hiromichi Kanehiro, Hideo Yagita, Yoshiyuki Nakajima. Nara Medical University, Nara, Japan, Juntendo University School of Medicine, Tokyo, Japan
The immune system mounts larger and more effective responses to previously exposed antigen by memory T cell. In tumor immunity, the effective in vivo induction of tumor antigen-specific memory T cell may be desirable strategy against various human malignancies. Recent studies have suggested that tumors might escape from host immunity through PD-L/PD-1 interaction that provides negative regulatory signal for T cell activation. We and others have recently found that PD-L/PD-1 pathway may play a pivotal role in some human malignancies. In this study, we extended our study to examine therapeutic efficacy of targeting T cell negative pathway in mice toward developing novel immunotherapy. To this end, we utilized murine syngeneic tumor models. CT26, a murine colon cancer, was inoculated into syngeneic BALB/c mice. We treated mice with anti-PD-1 (RMP1-14) and anti-CTLA-4 blocking mAb (4F10) in liver metastasis model. Interestingly, the coadministration of both mAbs displayed synergistic antitumor immunity and resulted in complete inhibition of liver metastasis, while monotherapy of each mAb had a modest antitumor effect. In addition, combined therapy of targeting PD-1 and CTLA-4 to the established advanced tumor induced substantial antitumor effect, thereby resulting in either complete rejection or significant inhibition in all treated mice. We further hypothesized that targeting T cell negative pathway before surgery might induce antigen-specific memory T cells and prevent postoperative tumor recurrence. To test this hypothesis, we treated mice with a single dose of anti-PD-1, anti-CTLA-4 mAb or control Ig when the tumor reached about 8 mm in diameter on the flank of mice. Tumors were completely resected 3 days after mAb treatment. Forty days later, we rechallenged CT26 in the opposite flank of mice. Rechallenged tumors established in 63% of mice treated with control IgG (n=30). In sharp contrast, they developed in only 20% of mice treated with anti-PD-1 mAb (n=10), 10% with anti-CTLA-4 mAb (n=10), and 5% of mice with simultaneous blockade of both mAbs (n=20). Thus, preoperative mAb treatment significantly prevented the establishment of rechallenged tumors compared to controls (P=0.04 versus PD-1 blockade, P=0.01 versus CTLA-4 blockade, P=0.0001 versus both PD-1/CTLA4 blockade, respectively). Furthermore, mechanistic analysis revealed that the treatment promoted the T cell infiltration, predominantly CD8+, into the tumor, thereby resulting in local immune activation as evidenced by the upregulation of Granzyme B and Perforin in tumors. In conclusion, we have demonstrated for the first time that blockade of differential T cell negative pathways of PD-L/PD-1 and B7/CTLA-4 evoked powerful as well as long-lasting tumor immunity in vivo. Thus, we suggest that this promising strategy is potentially effective in treatment of tumor recurrence, metastasis and advanced tumors in humans. |
