In vivo dendritic cell reprogramming for cancer immunotherapy.

Affiliations

• 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.
• Asgard Therapeutics AB, Medicon Village, 223 81 Lund, Sweden.
• InSphero AG, 8952 Schlieren, Switzerland.
• Department of Oncology, National Center of Cancer Immune Therapy (CCIT-DK), Copenhagen University Hospital, 2730 Herlev, Denmark.
• Department of Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark.
• Department of Otorhinolaryngology, Head & Neck Surgery, Skåne University Hospital, 221 85 Lund, Sweden.
• Department of Clinical Sciences, Lund University, 221 84 Lund, Sweden.
• Department of Immunotechnology, Lund University, Medicon Village, 223 81 Lund, Sweden.
• Centre for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês do Pombal, 3004-517 Coimbra, Portugal.

PMID:  39236156  DOI: 10.1126/science.adn9083

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.

免疫疗法可以让一些癌症患者获得长期生存的机会，但其普遍成功受到抗原呈递不足和免疫细胞被排除在肿瘤微环境之外的限制。我们开发了一种通过腺病毒传递转录因子PU.1、IRF8和BATF3在体内重编程肿瘤细胞的方法，使它们能够像1型常规树突细胞一样呈递抗原。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，诱导肿瘤退缩，并在多种小鼠黑色素瘤模型中建立了长期的系统免疫。在人类肿瘤球体和异种移植模型中，重编程为免疫原性树突细胞的过程不受通常限制免疫疗法的免疫抑制影响。我们的研究为人类临床试验中体内免疫细胞重编程用于癌症免疫疗法奠定了基础。