Cancer immunotherapy induces a tumor antigen-specific T lymphocyte response that kills tumor cells. Dendritic cells, specifically conventional type 1 dendritic cells (cDC1s), have a crucial role in antigen presentation, making them an important cell type for immunotherapy. Tumor cell reprogramming into cDC1-like cells by the transcription factors PU.1, IRF8 and BATF2 (PIB) results in robust T cell activation in vitro. Ascic et al. demonstrate that PIB-mediated cDC1 reprogramming triggers anti-tumor immunity and hampers tumor growth in melanoma mouse models. Moreover, it remodels the tumor microenvironment by increasing memory and stem-like T cell infiltration while reducing the exhausted population. Single-cell transcriptomics reveals expansion of the CD4⁺ T cell population, supporting PIB-mediated immunity. Among the gene therapy delivery strategies tested, adenoviral vectors show robust tumor transduction and reprogramming in situ, triggering an efficient T cell response in lymph nodes and tumors. As a result, mice remain tumor free and resistant to metastatic spreading. Importantly, PIB overexpression in human xenografts and tumor spheroids also induces cDC1 reprogramming and immunogenicity independently of immunosuppression. This study introduces a cDC1 reprogramming-based gene therapy approach that promotes long-term, safe and efficient anti-tumor immunity.

Original reference: Science https://doi.org/10.1126/science.adn9083 (2024)

癌症免疫疗法会诱导肿瘤抗原特异性 T 淋巴细胞反应，从而杀死肿瘤细胞。树突状细胞，特别是传统的 1 型树突状细胞 （cDC1），在抗原呈递中起着至关重要的作用，使其成为免疫治疗的重要细胞类型。转录因子 PU.1、IRF8 和 BATF2 （PIB） 将肿瘤细胞重编程为 cDC1 样细胞，从而在体外产生强大的 T 细胞活化。Ascic 等人证明，PIB 介导的 cDC1 重编程触发抗肿瘤免疫并阻碍黑色素瘤小鼠模型中的肿瘤生长。此外，它通过增加记忆和干细胞样 T 细胞浸润来重塑肿瘤微环境，同时减少耗尽的种群。单细胞转录组学揭示了 CD4⁺ T 细胞群的扩增，支持 PIB 介导的免疫。在测试的基因治疗递送策略中，腺病毒载体显示出强大的肿瘤转导和原位重编程，在淋巴结和肿瘤中触发有效的 T 细胞反应。因此，小鼠保持无肿瘤且对转移扩散具有抵抗力。重要的是，PIB 在人异种移植物和肿瘤球体中的过表达也会诱导 cDC1 重编程和免疫原性，而与免疫抑制无关。本研究介绍了一种基于 cDC1 重编程的基因治疗方法，可促进长期、安全和有效的抗肿瘤免疫。

Original reference: Science https://doi.org/10.1126/science.adn9083 (2024)