STAT3 inhibition in combination with CD47 blockade inhibits osteosarcoma lung metastasis
Pradeep Shrestha1, Rejeena Shrestha2, You Zhou1
1Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Background:
New therapies are urgently needed for patients with osteosarcoma (OS). STAT3 and CD47 are potential therapeutic target in OS. Here we investigated the therapeutic activity of the orally bioavailable STAT3 inhibitor, WP1066, and anti-CD47 antibody using OS mouse models.
Methods:
Cytotoxic effect of WP1066 against OS cell lines and its immunomodulatory effects were evaluated in vitro. Experimental metastasis and orthotopic syngeneic mouse models were used to investigate the therapeutic efficacy of WP1066 and anti-CD47 antibody. Further flow cytometric analysis was performed.
Results:
STAT3 was constitutively activated in multiple human and mouse OS cell lines. WP1066 suppressed STAT3 activation and induced apoptosis. WP1066 reduced the viability and proliferation of MDSCs and increased the expression level of MHC-II, and CD80 in macrophages. We demonstrated that WP1066 monotherapy prolonged the survival of mice with OS lung metastasis using an experimental metastasis and an orthotopic model. The therapeutic effect was significantly increased when WP1066 was combined with anti-CD47. This was associated with increased frequency of activated CD8+ T cells, NK cells and macrophages in the lungs and LDLNs.
Conclusion:
Our preclinical studies support further investigation of targeting STAT3 and CD47 as novel immunotherapeutic approach against OS lung metastasis.
Insights
New therapies targeting STAT3 and CD47 show promise for osteosarcoma (OS). Combining WP1066 with anti-CD47 antibody effectively reduced OS lung metastasis in mice, enhancing immune responses.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Osteosarcoma (OS) necessitates novel therapeutic strategies.
- Signal transducer and activator of transcription 3 (STAT3) and CD47 are identified as potential therapeutic targets in OS.
- This study investigates the combined therapeutic potential of WP1066, a STAT3 inhibitor, and an anti-CD47 antibody in OS models.
Purpose of the Study:
- To evaluate the in vitro cytotoxic and immunomodulatory effects of WP1066.
- To assess the in vivo therapeutic efficacy of WP1066 and anti-CD47 antibody, alone and in combination, against OS lung metastasis.
- To analyze the impact of these therapies on immune cell populations.
Main Methods:
- In vitro evaluation of WP1066's effects on OS cell lines and immune cells.
- In vivo studies utilizing experimental metastasis and orthotopic syngeneic mouse models of OS.
- Flow cytometric analysis to assess immune cell infiltration and activation.
Main Results:
- WP1066 inhibited STAT3 activation, induced apoptosis in OS cells, and modulated myeloid-derived suppressor cells (MDSCs) and macrophages.
- WP1066 monotherapy prolonged survival in mice with OS lung metastasis.
- Combination therapy with WP1066 and anti-CD47 significantly enhanced therapeutic efficacy, increasing activated CD8+ T cells, NK cells, and macrophages.
Conclusions:
- Targeting STAT3 with WP1066 and CD47 with an antibody represents a promising novel immunotherapeutic approach for osteosarcoma lung metastasis.
- Preclinical data support further clinical investigation of this combination strategy.
