Abstract 3224: Blocking FSTL1 reprograms cancer-caused abnormal immunity

Purposes: The close connection between imbalanced immunity and tumor progression has been increasingly recognized, and a number of inhibitors for blocking immune inhibitory checkpoints have been established to improve the anti-tumor immunity in cancer patients. However, clinical responses are limited to a part of the treated patients. We previously identified FSTL1, which is significantly secreted from Snail+ metastatic tumor cells, as a key effector molecule in the cancer-caused immune suppression and dysfunction. FSTL1 generates and expands pluripotent mesenchymal stem cells (MSCs), which are able to generate various immunoregulatory cells and functionally impaired CD8-low T cells, and also to induce de novo tumor dissemination into bone marrow. FSTL1 also directly confers higher invasiveness on tumor cells (EMT induction). To prevent the FSTL1-caused vicious circulation for tumor progression, we attempted to establish anti-FSTL1 blocking mAbs. Results: We generated chicken/mouse chimeric anti-FSTL1 mAbs, which specifically recognized human and mouse FSTL1. The anti-FSTL1 mAb significantly suppressed tumor proliferation and invasion, MSC induction in mouse bone marrow cells, and Treg induction in human PBMCs in vitro as compared to the control group. When bone metastatic melanoma models (C57BL/6 mice implanted with snail-transduced B16-F10 melanoma cells both subcutaneously and intravenously) were intraperitoneally injected with the anti-FSTL1 mAb (10 mg/kg) on Day 5 (when tumor metastasis was already observed in bone marrow) and Day 10 after tumor implantation, the FSTL1-caused events were inhibited, and tumor-specific CD8+ T cells with higher CTL activities were generated, resulting in significant suppression of subcutaneous tumor growth and bone metastasis in the treated mice as compared to those of the control mice. At least in the same models, conventional immune checkpoint inhibitors including anti-CTLA4, anti-PD1, and anti-PDL1 mAbs failed to improve the anti-tumor immunity, and rather promoted bone metastasis because of no reduction of regulatory cells, particularly the MSCs in the treated mice. Conclusions: These results suggest that blocking FSTL1 reprograms and properly induces anti-tumor immunity by switching the tumor-supportive immune directivity to the active mode against cancer. Our anti-FSTL1 mAb having totally different molecular mechanisms from the conventional ones may be a promising therapeutics as a next generation of “immune checkpoint inhibitors” for radically correcting cancer-manipulated immunity in clinical settings. Citation Format: Chie Kudo-Saito, Masayoshi Toyoura, Yuji Shoya, Akiko Ishida, Ryoko Kon. Blocking FSTL1 reprograms cancer-caused abnormal immunity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3224.