Molecular Therapy: Oncolytics (Sep 2022)

Galectin-3 inhibition boosts the therapeutic efficacy of Semliki Forest virus in pediatric osteosarcoma

  • Guillermo Herrador-Cañete,
  • Marta Zalacain,
  • Sara Labiano,
  • Virginia Laspidea,
  • Montserrat Puigdelloses,
  • Lucía Marrodan,
  • Marc Garcia-Moure,
  • Marisol Gonzalez-Huarriz,
  • Javier Marco-Sanz,
  • Iker Ausejo-Mauleon,
  • Daniel de la Nava,
  • Reyes Hernández-Osuna,
  • Javier Martínez-García,
  • Noelia Silva-Pilipich,
  • Elisabeth Gurucega,
  • Ana Patiño-García,
  • Rubén Hernández-Alcoceba,
  • Cristian Smerdou,
  • Marta M. Alonso

Journal volume & issue
Vol. 26
pp. 246 – 264

Abstract

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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.

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