Di Grazia Antonio, Franzè Eleonora, Frascatani Rachele, Laudisi Federica, Pacifico Teresa, Tomassini Lorenzo, Di Fusco Davide, Formica Vincenzo, Sica Giuseppe, Stolfi Carmine, Monteleone Ivan, Monteleone Giovanni
Department of Systems Medicine, University of Rome "Tor Vergata", Via Montpellier, 1, 00133, Rome, Italy.
Medical Oncology Unit, Fondazione Policlinico "Tor Vergata", Rome, Italy.
Exp Hematol Oncol. 2024 Sep 27;13(1):95. doi: 10.1186/s40164-024-00562-y.
Interactions between colorectal cancer (CRC) cells and the noncancerous cells in the tumor microenvironment (TME) induce mechanisms for the escape of tumor cells from immune attack. Hepcidin, a peptide that controls immune cell functions, is overproduced by CRC cells. This study aimed to evaluate whether hepcidin acts as a regulator of anti-tumor immunity in CRC. Hepcidin silencing in CRC cells was followed by enhanced TNF-driven caspase-dependent cleavage of GSDM E and death. Mice engrafted with hepcidin-deficient CT26 cells developed fewer and smaller tumors than control mice as a result of the action of tumor-infiltrating CD8+ T lymphocytes and were protected from the development of tumors in a vaccination model and exhibited long-lasting tumor protection. Additionally, hepcidin deficiency enhanced the response of mice bearing CT26-derived tumors to anti-PD-1 therapy. These results suggest that targeting hepcidin in CRC cells enhances the production of TNF thereby triggering a caspase/GSDM E-driven lytic cell death with the downstream effect of boosting a robust immune response against tumor antigens.
结直肠癌（CRC）细胞与肿瘤微环境（TME）中的非癌细胞之间的相互作用诱导了肿瘤细胞逃避免疫攻击的机制。铁调素是一种控制免疫细胞功能的肽，由CRC细胞过度产生。本研究旨在评估铁调素是否作为CRC中抗肿瘤免疫的调节剂。CRC细胞中铁调素沉默后，TNF驱动的GSDM E的半胱天冬酶依赖性切割增强并导致细胞死亡。由于肿瘤浸润性CD8 + T淋巴细胞的作用，移植了铁调素缺陷型CT26细胞的小鼠比对照小鼠产生的肿瘤更少且更小，并且在疫苗接种模型中免受肿瘤发展的影响，并表现出持久的肿瘤保护作用。此外，铁调素缺乏增强了携带CT26衍生肿瘤的小鼠对抗PD-1治疗的反应。这些结果表明，靶向CRC细胞中的铁调素可增强TNF的产生，从而触发半胱天冬酶/GSDM E驱动的溶细胞死亡，其下游效应是增强针对肿瘤抗原的强大免疫反应。
