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Blocking FSTL1 boosts NK immunity in treatment of osteosarcoma
Yamato Ogiwara1, Makoto Nakagawa2, Fumihiko Nakatani3
1Department of Immune Medicine, National Cancer Center Research Institute, Tokyo, 104-0045, Japan.
Abstract:
Osteosarcoma (OS) is the most common primary bone malignancy. Many patients develop relapse and metastasis after treatments, and more effective treatments are needed for improving the clinical outcome. FSTL1 overexpression has been reported in murine and human OS, while the functional roles of FSTL1 remain unclear. Here, we elucidated tumor biological and immunological mechanisms underlying the refractory OS using mouse and human OS cell lines, mouse OS models, and clinical specimens. FSTL1 knockout in OS cells significantly suppressed cellular functions, including proliferation, invasion, sphere colony formation, and ALCAM expression. The FSTL1-ablated tumor cells were completely rejected due to generation of potent NK cells in the in vivo setting. Indeed, FSTL1 stimulation suppressed NK activity partly via apoptosis induction, but blocking FSTL1 or CD6, a receptor for ALCAM, significantly restored NK activity. Anti-FSTL1 therapy significantly suppressed tumor growth and metastasis in mouse OS models, and synergized with anti-CD6 therapy in providing significantly better prognosis. These suggest that blocking FSTL1 is a promising strategy for successfully treating OS. This study demonstrates a rationale of targeting the FSTL1-ALCAM axis in the treatment of OS in clinical settings.
Insights
Blocking FSTL1 shows promise for treating osteosarcoma (OS). This approach enhances natural killer (NK) cell activity, suppresses tumor growth, and reduces metastasis, offering a new therapeutic strategy for this bone cancer.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Osteosarcoma (OS) is a common bone cancer with high rates of relapse and metastasis.
- The role of FSTL1 in OS progression and treatment resistance is not well understood.
Purpose of the Study:
- To investigate the biological and immunological mechanisms of refractory OS.
- To evaluate the therapeutic potential of targeting FSTL1 in OS treatment.
Main Methods:
- Utilized human and mouse OS cell lines, mouse OS models, and clinical specimens.
- Performed FSTL1 knockout experiments and assessed cellular functions (proliferation, invasion, sphere formation).
- Investigated the impact of FSTL1 on Natural Killer (NK) cell activity and the FSTL1-ALCAM-CD6 axis.
Main Results:
- FSTL1 knockout suppressed OS cell proliferation, invasion, and ALCAM expression.
- FSTL1-ablated tumor cells were rejected in vivo due to enhanced NK cell activity.
- Blocking FSTL1 or CD6 restored NK cell activity suppressed by FSTL1.
- Anti-FSTL1 therapy reduced tumor growth and metastasis in mouse models, synergizing with anti-CD6 therapy.
Conclusions:
- Targeting the FSTL1-ALCAM axis is a promising therapeutic strategy for osteosarcoma.
- Blocking FSTL1 enhances NK cell-mediated anti-tumor immunity, overcoming treatment resistance.
- This study provides a rationale for clinical application of anti-FSTL1 therapies in OS treatment.
