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Galectin-3 inhibition boosts the therapeutic efficacy of Semliki Forest virus in pediatric osteosarcoma
Guillermo Herrador-Cañete1,2,3, Marta Zalacain1,2,4, Sara Labiano1,2,4
1Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.
Abstract:
The outcomes of metastatic and nonresponder pediatric osteosarcoma patients are very poor and have not improved in the last 30 years. These tumors harbor a highly immunosuppressive environment, making existing immunotherapies ineffective. Here, we evaluated the use of Semliki Forest virus (SFV) vectors expressing galectin-3 (Gal3) inhibitors as therapeutic tools, since both the inhibition of Gal3, which is involved in immunosuppression and metastasis, and virotherapy based on SFV have been demonstrated to reduce tumor progression in different tumor models. In vitro, inhibitors based on the Gal3 amino-terminal domain alone (Gal3-N) or fused to a Gal3 peptide inhibitor (Gal3-N-C12) were able to block the binding of Gal3 to the surface of activated T cells. In vivo, SFV expressing Gal3-N-C12 induced strong antitumor responses in orthotopic K7M2 and MOS-J osteosarcoma tumors, leading to complete regressions in 47% and 30% of mice, respectively. Pulmonary metastases were also reduced in K7M2 tumor-bearing mice after treatment with SFV-Gal3-N-C12. Both the antitumor and antimetastatic responses were dependent on modulation of the immune system, primarily including an increase in tumor-infiltrating lymphocytes and a reduction in the immunosuppressive environment inside tumors. Our results demonstrated that SFV-Gal3-N-C12 could constitute a potential therapeutic agent for osteosarcoma patients expressing Gal3.
Insights
New Semliki Forest virus (SFV) therapy targeting galectin-3 (Gal3) shows promise for pediatric osteosarcoma. SFV-Gal3-N-C12 effectively reduced tumors and metastases by modulating the immune system, offering hope for difficult-to-treat cases.
Area of Science:
- Oncology
- Immunotherapy
- Virology
Background:
- Pediatric osteosarcoma, particularly metastatic or nonresponder cases, has poor outcomes with no recent therapeutic advancements.
- Osteosarcoma tumors create an immunosuppressive environment, hindering the effectiveness of current immunotherapies.
- Galectin-3 (Gal3) plays a role in tumor immunosuppression and metastasis, making it a potential therapeutic target.
Purpose of the Study:
- To evaluate Semliki Forest virus (SFV) vectors expressing galectin-3 (Gal3) inhibitors as a novel therapeutic strategy for pediatric osteosarcoma.
- To assess the efficacy of Gal3 inhibitors, specifically Gal3-N and Gal3-N-C12, in blocking Gal3 interactions with T cells.
- To determine the in vivo antitumor and antimetastatic effects of SFV-mediated delivery of Gal3 inhibitors in osteosarcoma models.
Main Methods:
- In vitro assessment of Gal3 inhibitors (Gal3-N, Gal3-N-C12) for their ability to block Gal3 binding to activated T cells.
- In vivo evaluation of SFV expressing Gal3-N-C12 in orthotopic K7M2 and MOS-J osteosarcoma mouse models.
- Analysis of immune system modulation, including tumor-infiltrating lymphocytes and the tumor microenvironment, following treatment.
Main Results:
- Gal3-N and Gal3-N-C12 inhibitors effectively blocked Gal3 binding to activated T cells in vitro.
- SFV-Gal3-N-C12 treatment resulted in complete tumor regressions in 47% (K7M2) and 30% (MOS-J) of mice.
- Pulmonary metastases were significantly reduced in K7M2 tumor-bearing mice treated with SFV-Gal3-N-C12.
- Therapeutic effects were linked to immune system modulation, including increased tumor-infiltrating lymphocytes and a less immunosuppressive tumor environment.
Conclusions:
- SFV vectors expressing Gal3 inhibitors, particularly SFV-Gal3-N-C12, demonstrate significant antitumor and antimetastatic activity in preclinical osteosarcoma models.
- The observed responses are immune-mediated, highlighting the potential of combining virotherapy with immunotherapy.
- SFV-Gal3-N-C12 represents a promising therapeutic candidate for pediatric osteosarcoma patients with Gal3-expressing tumors.
