当前位置: X-MOL 学术EMBO Mol. Med. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Myeloid cell-based delivery of IFN-γ reprograms the leukemia microenvironment and induces anti-tumoral immune responses
EMBO Molecular Medicine ( IF 9.0 ) Pub Date : 2021-08-30 , DOI: 10.15252/emmm.202013598
Adele Mucci 1 , Gabriele Antonarelli 1, 2 , Carolina Caserta 1 , Francesco Maria Vittoria 1, 2 , Giacomo Desantis 1 , Riccardo Pagani 1, 2 , Beatrice Greco 3 , Monica Casucci 3 , Giulia Escobar 1 , Laura Passerini 1 , Nico Lachmann 4 , Francesca Sanvito 5 , Matteo Barcella 1, 6 , Ivan Merelli 6 , Luigi Naldini 1, 2 , Bernhard Gentner 1, 7
Affiliation  

The immunosuppressive microenvironment surrounding tumor cells represents a key cause of treatment failure. Therefore, immunotherapies aimed at reprogramming the immune system have largely spread in the past years. We employed gene transfer into hematopoietic stem and progenitor cells to selectively express anti-tumoral cytokines in tumor-infiltrating monocytes/macrophages. We show that interferon-γ (IFN-γ) reduced tumor progression in mouse models of B-cell acute lymphoblastic leukemia (B-ALL) and colorectal carcinoma (MC38). Its activity depended on the immune system's capacity to respond to IFN-γ and drove the counter-selection of leukemia cells expressing surrogate antigens. Gene-based IFN-γ delivery induced antigen presentation in the myeloid compartment and on leukemia cells, leading to a wave of T cell recruitment and activation, with enhanced clonal expansion of cytotoxic CD8+ T lymphocytes. The activity of IFN-γ was further enhanced by either co-delivery of tumor necrosis factor-α (TNF-α) or by drugs blocking immunosuppressive escape pathways, with the potential to obtain durable responses.

中文翻译:

基于骨髓细胞的 IFN-γ 递送重新编程白血病微环境并诱导抗肿瘤免疫反应

肿瘤细胞周围的免疫抑制微环境是治疗失败的关键原因。因此,旨在重新编程免疫系统的免疫疗法在过去几年中得到了广泛传播。我们将基因转移到造血干细胞和祖细胞中,以在肿瘤浸润的单核细胞/巨噬细胞中选择性表达抗肿瘤细胞因子。我们发现,干扰素-γ (IFN-γ) 可减少 B 细胞急性淋巴细胞白血病 (B-ALL) 和结直肠癌 (MC38) 小鼠模型中的肿瘤进展。其活性取决于免疫系统对 IFN-γ 的反应能力,并驱动表达替代抗原的白血病细胞的反选择。基于基因的 IFN-γ 递送诱导骨髓区室和白血病细胞上的抗原呈递,导致 T 细胞招募和激活浪潮,并增强细胞毒性 CD8 + T 淋巴细胞的克隆扩增。通过联合递送肿瘤坏死因子-α (TNF-α) 或阻断免疫抑制逃逸途径的药物,可以进一步增强 IFN-γ 的活性,并有可能获得持久的反应。
更新日期:2021-10-07
down
wechat
bug