Molecular Medicine and Gene Therapy, Lund Stem Cell Centre, Lund University, 221 84 Lund, Sweden.
Wallenberg Centre for Molecular Medicine at Lund University, 221 84 Lund, Sweden.
Science. 2024 Oct 18;386(6719):eadn9083. doi: 10.1126/science.adn9083.
Immunotherapy can lead to long-term survival for some cancer patients, yet generalized success has been hampered by insufficient antigen presentation and exclusion of immunogenic cells from the tumor microenvironment. Here, we developed an approach to reprogram tumor cells in vivo by adenoviral delivery of the transcription factors PU.1, IRF8, and BATF3, which enabled them to present antigens as type 1 conventional dendritic cells. Reprogrammed tumor cells remodeled their tumor microenvironment, recruited, and expanded polyclonal cytotoxic T cells; induced tumor regressions; and established long-term systemic immunity in multiple mouse melanoma models. In human tumor spheroids and xenografts, reprogramming to immunogenic dendritic-like cells progressed independently of immunosuppression, which usually limits immunotherapy. Our study paves the way for human clinical trials of in vivo immune cell reprogramming for cancer immunotherapy.
免疫疗法可以使一些癌症患者长期存活，但由于抗原呈递不足以及免疫原性细胞从肿瘤微环境中被排除，普遍的成功受到了阻碍。在这里，我们通过腺病毒递送转录因子 PU.1、IRF8 和 BATF3 来开发一种在体内重编程肿瘤细胞的方法，使它们能够作为 1 型传统树突状细胞呈递抗原。重编程的肿瘤细胞重塑了它们的肿瘤微环境，招募并扩增了多克隆细胞毒性 T 细胞；诱导肿瘤消退；并在多种小鼠黑色素瘤模型中建立了长期的系统性免疫。在人肿瘤球体和异种移植物中，免疫原性树突状样细胞的重编程进展独立于免疫抑制，免疫抑制通常限制免疫疗法。我们的研究为癌症免疫疗法中体内免疫细胞重编程的人类临床试验铺平了道路。
