Abstract LB-310: Overcoming resistance of conventional therapies by targeting cancer-associated fibroblasts (CAFs) with near-infrared photoimmunotherapy (NIR-PIT)
Authors: Komoto Satoshi , Noma Kazuhiro , Katsube Ryoichi , Kato Takuya , Ohara Toshiaki , Sato Hiroaki , Narusaka Toru , Nisiwaki Noriyuki , Tazawa Hiroshi , Shirakawa Yasuhiro , Fujiwara Toshiyoshi 
Published: August 2019

Esophageal cancer is known to one of the most aggressive malignant tumors, however, the effect of conventional chemotherapy and radiotherapy is insufficiently. Cancer-associated fibroblasts (CAFs) are thought to play an essential role in cancer invasion, migration, metastasis, immunosuppression, and resistance to anticancer drugs. Previously, we have developed a novel near-infrared photoimmunotherapy (NIR-PIT) targeting CAFs, which induces the selective destruction by targeting specific surface protein of CAFs; fibroblast activation protein (FAP). The aim of this study is to analyze the influence of CAFs for human esophageal cancer and to evaluate the improvement of conventional therapeutic resistance using NIR-PIT targeting CAFs.We produced the IR700-FAP antibody for this study. Human esophageal cancer cell lines (TE4 and OE19) and FEF3 human fibroblasts were used. At first, we demonstrated that cancer cells stimulated by CAFs acquired resistance to conventional therapies by cell viability assay. Furthermore, invasion, migration, and colony-formation assays demonstrated the CAF-stimulated cancer cells had a more malignant phenotype. Western blotting analysis showed that E-cadherin expression was decreased and vimentin expression was increased in CAF-stimulated cancer cells, indicating the epithelial mesenchymal transition induction. In vivo experiments demonstrated that subcutaneous tumors co-injected with CAFs were more refractory to chemotherapy than the tumors without CAFs as same as observed in vitro. Secondary, we found that acquired therapeutic resistance in stimulated cancer cells were restored by excluding continuous stimulation of CAFs. Finally, we investigated whether depleting CAFs by NIR-PIT could affect the chemo-resistance of cancer cells in vitro and in vivo. To evaluate the combination effect of conventional chemotherapy and NIR-PIT in vivo, xenograft models co-injected TE4 cells with CAFs were treated with 5-FU plus NIR-PIT, 5-FU alone, or PBS as control. 5-FU alone therapy could not suppress tumor growth, however combination therapy as 5-FU plus NIR-PIT could suppress tumor growth compared to control significantly. These results demonstrated that CAFs gave human esophageal cancer cells higher malignant and resistant phenotype, which could be overcome by using NIR-PIT targeting CAFs. Targeting fibroblast itself is a unique strategy and can be clinically promising as combination targeting cancer cells and their fundamental microenvironment, CAFs.

Citation Format: Satoshi Komoto, Kazuhiro Noma, Ryoichi Katsube, Takuya Kato, Toshiaki Ohara, Hiroaki Sato, Toru Narusaka, Noriyuki Nisiwaki, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Overcoming resistance of conventional therapies by targeting cancer-associated fibroblasts (CAFs) with near-infrared photoimmunotherapy (NIR-PIT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-310.