Abstract
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.
摘要
免疫疗法可以为部分癌症患者带来长期生存机会，但其广泛成功受限于抗原呈递不足和免疫原性细胞被排除在肿瘤微环境之外。在此研究中，我们开发了一种通过腺病毒递送转录因子PU.1、IRF8和BATF3的方式，在体内重编程肿瘤细胞的方法，使其能够像I型常规树突状细胞一样呈递抗原。重编程后的肿瘤细胞重塑了肿瘤微环境，招募并扩展了多克隆细胞毒性T细胞，诱导了肿瘤回归，并在多个小鼠黑色素瘤模型中建立了长期的系统性免疫。在人类肿瘤球体和异种移植模型中，向具有免疫原性的类树突状细胞的重编程独立于通常限制免疫疗法的免疫抑制机制进行。我们的研究为在体内免疫细胞重编程用于癌症免疫疗法的临床试验铺平了道路。
原文链接
Ascic E, Åkerström F, Sreekumar Nair M, Rosa A, Kurochkin I, Zimmermannova O, Catena X, Rotankova N, Veser C, Rudnik M, Ballocci T, Schärer T, Huang X, de Rosa Torres M, Renaud E, Velasco Santiago M, Met Ö, Askmyr D, Lindstedt M, Greiff L, Ligeon LA, Agarkova I, Svane IM, Pires CF, Rosa FF, Pereira CF. In vivo dendritic cell reprogramming for cancer immunotherapy. Science. 2024 Oct 18;386(6719):eadn9083. doi: 10.1126/science.adn9083. Epub 2024 Oct 18. PMID: 39236156.
