Purposes: Osteosarcoma is a rare malignant tumor of bone in children and young adults, and it is very hard to successfully control the systemic metastases and life-threatening health problems more than a decade after the completion of the care due to the intensiveness of the conventional treatments including surgical resection of the primary tumor and chemotherapy. Therefore, non/low-toxic but advanced treatments have been expected for a long while. We recently found that a BMP family FSTL1 is highly and functionally expressed in murine and human osteosarcoma cell lines, and systemically expands pluripotent mesenchymal stem/stromal cells (MSCs), which play a central role in amplification of tumor heterogeneity that is consequence of reciprocal evolution together with the tumor microenvironment, including induction of immune suppression and dysfunction, desmoplasia, and angiogenesis. FSTL1 and its induced MSCs also directly confer higher invasive and metastatic properties on tumor cells leading to further cancer progression. In this study, we evaluated antitumor efficacy induced by anti-FSTL1 mAb on murine osteosarcoma models, and also compared the therapeutic efficacy with those induced by immune checkpoint inhibitory mAbs (ICIs).

Results: We used two syngeneic tumor models that were subcutaneously implanted with murine osteosarcoma NHOS cells in BALB/c mice, or LM3 cells in C3H mice. These mice were intraperitoneally injected with anti-FSTL1 mAbs (10mg/kg) twice on day 5 and day 8 after tumor implantation, and were sacrificed for immunological analysis of tumor-infiltrating cells, spleen cells and bone marrow cells on day 15. In both osteosarcoma models, CD45- MSCs as well as other immunosuppressive CD4+Foxp3+ Tregs and CD11b+Gr1+ MDSCs systemically increased, indicating impairment of antitumor immunity in the mice. Treatment with the anti-FSTL1 mAb significantly induced potent tumor-specific CTLs through reduction of MSCs, resulting in tumor-free in some of the treated mice. Although the antitumor efficacy was similar to those induced by ICIs, the mode of action was totally distinct because MSCs and the MSC-inducible exhausted CD8+PD1+Tim3+ T cells were reduced only in the anti-FSTL1-treated mice, but not in the ICI-treated mice.

Conclusions: These results suggest that blocking FSTL1 properly reprograms immunity toward elimination of osteosarcoma by reducing the tumor-supportive MSCs. Anti-FSTL1 mAb may be a promising drug for treating osteosarcoma more moderately but effectively in clinical settings.

Citation Format: Chie Kudo-Saito, Yamato Ogiwara, Kazunori Aoki. Blocking FSTL1 ameliorates immunity against osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4701. doi:10.1158/1538-7445.AM2017-4701