Herrador-Cañete Guillermo, Zalacain Marta, Labiano Sara, Laspidea Virginia, Puigdelloses Montserrat, Marrodan Lucía, Garcia-Moure Marc, Gonzalez-Huarriz Marisol, Marco-Sanz Javier, Ausejo-Mauleon Iker, de la Nava Daniel, Hernández-Osuna Reyes, Martínez-García Javier, Silva-Pilipich Noelia, Gurucega Elisabeth, Patiño-García Ana, Hernández-Alcoceba Rubén, Smerdou Cristian, Alonso Marta M
Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.
Solid Tumor Program, Cima Universidad de Navarra, Pamplona 31008, Spain.
Mol Ther Oncolytics. 2022 Jul 9;26:246-264. doi: 10.1016/j.omto.2022.07.004. eCollection 2022 Sep 15.
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. , 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. , 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.
转移性和无反应性小儿骨肉瘤患者的预后非常差，在过去30年中没有改善。这些肿瘤具有高度免疫抑制环境，使得现有的免疫疗法无效。在此，我们评估了表达半乳糖凝集素-3（Gal3）抑制剂的Semliki森林病毒（SFV）载体作为治疗工具的用途，因为抑制参与免疫抑制和转移的Gal3以及基于SFV的病毒疗法已被证明在不同肿瘤模型中可减少肿瘤进展。仅基于Gal3氨基末端结构域（Gal3-N）或与Gal3肽抑制剂融合（Gal3-N-C12）的抑制剂能够阻断Gal3与活化T细胞表面的结合。表达Gal3-N-C12的SFV在原位K7M2和MOS-J骨肉瘤肿瘤中诱导了强烈的抗肿瘤反应，分别导致47%和30%的小鼠完全消退。用SFV-Gal3-N-C12治疗后，K7M2荷瘤小鼠的肺转移也减少了。抗肿瘤和抗转移反应均依赖于免疫系统的调节，主要包括肿瘤浸润淋巴细胞的增加和肿瘤内部免疫抑制环境的减少。我们的结果表明，SFV-Gal3-N-C12可能成为表达Gal3的骨肉瘤患者的潜在治疗药物。
