Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Kraków, Poland.
Translational Nanobiomaterials and Imaging, Department of Radiology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands.
Arch Immunol Ther Exp (Warsz). 2024 Jan 6;72(1). doi: 10.2478/aite-2024-0002. eCollection 2024 Jan 1.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis of sensitive cancer cells, including colorectal cancer (CRC). Due to its short biological half-life after intravenous administration and related clinical ineffectiveness, novel formulations of TRAIL need to be developed. Here we propose bacteria as a vehicle for local delivery of human soluble TRAIL (hsTRAIL) in CRC. The use of common probiotics targeting guts as carriers for TRAIL could ensure its sustained release at the tumor site and extend the duration of its activity. We have already engineered hsTRAIL-secreting bacteria and showed their effectiveness in elimination of human CRC cells in vitro and in vivo in a mouse subcutaneous model. Here, (hsTRAIL+) were administered by gastric gavage to SCID mice with orthotopically developed HCT116 tumor in cecum, in monotherapy or in combination with metformin (MetF), already shown to enhance the hsTRAIL anti-tumor activity in subcutaneous CRC model. Oral administration of (hsTRAIL+) resulted in significant progression of HCT116 tumors and shortening of the colon crypts. Secretion of hsTRAIL in the colon was accompanied by infiltration of the primary tumor with M2-macrophages, while MetF promoted transient colonization of the gut by . Our study indicates that bacteria after oral administration enable delivery of biologically active hsTRAIL to colon, however its potential therapeutic effect in CRC treatment is abolished by its pro-tumorigenic signalling, leading to the recruitment of M2-macrophages and tumor growth promotion.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）选择性诱导包括结直肠癌（CRC）在内的敏感癌细胞凋亡。由于其静脉给药后的生物半衰期短，且相关临床效果不佳，因此需要开发 TRAIL 的新型制剂。在这里，我们提出利用细菌作为载体，将人源可溶性 TRAIL（hsTRAIL）递送至 CRC 局部。将靶向肠道的常用益生菌用作 TRAIL 的载体，可以确保其在肿瘤部位的持续释放，并延长其活性持续时间。我们已经构建了分泌 hsTRAIL 的细菌，并在体外和小鼠皮下模型中显示了其消除人 CRC 细胞的有效性。在这里，将（hsTRAIL+）通过灌胃给予盲肠原位发展 HCT116 肿瘤的 SCID 小鼠，单独治疗或与二甲双胍（MetF）联合治疗，MetF 已被证明可增强皮下 CRC 模型中 hsTRAIL 的抗肿瘤活性。（hsTRAIL+）的口服给药导致 HCT116 肿瘤的显著进展和结肠隐窝缩短。hsTRAIL 在结肠中的分泌伴随着 M2-巨噬细胞浸润原发性肿瘤，而 MetF 促进了细菌在肠道的短暂定植。我们的研究表明，口服给药后的细菌能够将生物活性 hsTRAIL 递送至结肠，但其促进肿瘤生长的促肿瘤信号转导作用，导致 M2-巨噬细胞的募集和肿瘤生长促进，从而消除了其在 CRC 治疗中的潜在治疗效果。
