New insights into targeting T cell negative pathway in tumor immunity
Abstract Number: 4985
Author Block:
Masayuki Sho, Takeo Nomi, Takahiro Akahori, Ichiro Yamato, Hiromichi Kanehiro, Miyuki Azuma, Hisaya Akiba, Hideo Yagita, Yoshiyuki Nakajima. Department of Surgery, Nara Medical University, Nara, Japan, Tokyo Medical and Dental University, Tokyo, Japan, Juntendo University School of Medicine, Tokyo, Japan
Recent studies have suggested that T cell negative regulatory pathways, including PD-1 and CTLA-4, play critical roles in tumor immunity and are potential targets for cancer immunotherapy. The efficacy of humanized anti-CTLA-4 or anti-PD-1 Ab is currently under investigation in several clinical trials. Although significant but limited antitumor effect have been reported, further studies are required to enhance the clinical response. Toward clinical application, we extended our study to examine several novel strategies targeting T cell negative pathway. We have recently reported that PD-L expression has a significant prognostic value in pancreatic and esophageal cancer, suggesting that PD-L/PD-1 is functionally important in human cancer. In murine tumor models, anti-PD-1 (RMP1-14) and anti-CTLA-4 (4F10) 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. By histology, extensive cell recruitments and necrosis in the established tumor in treated mice were observed. 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 IFN-gamma, Granzyme B, and Perforin. 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. In addition, we also evaluated recently identified T cell negative pathways, including B7-H3 and TIM-3/Galectin-9 (Gal-9). B7-H3, TIM-3, and Gal-9 were expressed in human malignancies including pancreatic cancer. Interestingly, anti-B7-H3 (MJ-18), anti-TIM-3 (RMT3-23) and anti-Gal-9 (RG9-35) blocking mAbs had also significant antitumor effect in vivo, similar to PD-1 and CTLA-4 blockade. Toward clinical application, we examined the efficacy of combination therapy of blocking T cell negative pathways with conventional chemotherapy. The combined use of gemcitabine significantly synergized with blocking PD-1/PD-L, B7-H3, and TIM-3/Galectin-9 pathway, resulting in substantial tumor regression. In summary, our clinical and experimental data demonstrated several novel findings as follows: (1) simultaneous blockade of differential T cell negative pathways evoked powerful and long-lasting tumor immunity, (2) the effect of blocking various negative pathways was synergistically enhanced by combining chemotherapy, (3) several novel negative pathways have also therapeutic potential against intractable cancer. In conclusion, a series of our studies provides new insights into targeting T cell negative pathway in tumor immunity and suggests that these promising strategies are potentially effective in human cancers. |
