Riviere Clément, Aljieli Muna, Mévélec Marie-Noëlle, Lantier Louis, Boursin Fanny, Lajoie Laurie, Ducournau Céline, Germon Stéphanie, Moiré Nathalie, Dimier-Poisson Isabelle, Aubrey Nicolas, di Tommaso Anne
BioMAP, UMR ISP 1282 INRAe - Université de Tours, 37200 Tours, France.
Faculty of Pharmacy, University of Gezira, Wad Madani, Sudan.
Mol Ther Oncol. 2025 Mar 19;33(2):200968. doi: 10.1016/j.omton.2025.200968. eCollection 2025 Jun 18.
, a potential anticancer agent able to reactivate the immune response within the tumor microenvironment (TME), has recently shown enhanced immunomodulatory properties in different tumor models when armed with the cytokine, Il-15. In the current area of combination immunotherapy strategies designed to overcome treatment resistance, we engineered for the first time the protozoan to vectorize and secrete a single-chain variable fragment fused to fragment crystallizable region (scFv-Fc) targeting human programmed cell death ligand 1 (PD-L1). Following validation of its secretion through the micronemes (protozoa secretory organelles), we demonstrated that the scFv-Fc could bind PD-L1 on mouse and human tumor cells, block the programmed cell death protein 1 (PD-1)/PD-L1 pathway leading to potentiate the T cell lymphocyte activity. Additionally, the scFv-Fc induced antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC). Those data demonstrate the feasibility of vectoring and secreting a functional antibody fragment by opening promising avenues for future research.
作为一种能够在肿瘤微环境（TME）中重新激活免疫反应的潜在抗癌剂，最近在携带细胞因子白细胞介素-15（Il-15）时，在不同肿瘤模型中显示出增强的免疫调节特性。在当前旨在克服治疗抗性的联合免疫治疗策略领域，我们首次对原生动物进行工程改造，使其将靶向人程序性细胞死亡配体1（PD-L1）的与可结晶片段融合的单链可变片段（scFv-Fc）进行载体化并分泌。在通过微线体（原生动物分泌细胞器）验证其分泌后，我们证明scFv-Fc可以结合小鼠和人类肿瘤细胞上的PD-L1，阻断程序性细胞死亡蛋白1（PD-1）/PD-L1途径，从而增强T细胞淋巴细胞活性。此外，scFv-Fc诱导抗体依赖性细胞吞噬作用（ADCP）和抗体依赖性细胞毒性（ADCC）。这些数据证明了通过原生动物载体化和分泌功能性抗体片段的可行性，为未来的研究开辟了有希望的途径。
