Targeted Cancer Gene Therapy Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita Salute San Raffaele University, 20132 Milan, Italy.
Targeted Cancer Gene Therapy Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Bioinformatics Core, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
Cancer Cell. 2023 Nov 13;41(11):1892-1910.e10. doi: 10.1016/j.ccell.2023.09.014. Epub 2023 Oct 19.
Liver metastases are associated with poor response to current pharmacological treatments, including immunotherapy. We describe a lentiviral vector (LV) platform to selectively engineer liver macrophages, including Kupffer cells and tumor-associated macrophages (TAMs), to deliver type I interferon (IFNα) to liver metastases. Gene-based IFNα delivery delays the growth of colorectal and pancreatic ductal adenocarcinoma liver metastases in mice. Response to IFNα is associated with TAM immune activation, enhanced MHC-II-restricted antigen presentation and reduced exhaustion of CD8 T cells. Conversely, increased IL-10 signaling, expansion of Eomes CD4 T cells, a cell type displaying features of type I regulatory T (Tr1) cells, and CTLA-4 expression are associated with resistance to therapy. Targeting regulatory T cell functions by combinatorial CTLA-4 immune checkpoint blockade and IFNα LV delivery expands tumor-reactive T cells, attaining complete response in most mice. These findings support a promising therapeutic strategy with feasible translation to patients with unmet medical need.
肝转移与当前包括免疫疗法在内的药物治疗反应不佳相关。我们描述了一种慢病毒载体 (LV) 平台，用于选择性地对肝脏巨噬细胞（包括枯否细胞和肿瘤相关巨噬细胞[TAMs]）进行工程改造，以将 I 型干扰素 (IFNα) 递送至肝转移部位。基于基因的 IFNα 递送可延缓结直肠癌和胰腺导管腺癌肝转移在小鼠中的生长。对 IFNα 的反应与 TAM 免疫激活、增强 MHC-II 限制的抗原呈递以及减少 CD8 T 细胞耗竭有关。相反，增加的 IL-10 信号传导、Eomes CD4 T 细胞的扩增（一种具有 I 型调节性 T（Tr1）细胞特征的细胞类型）和 CTLA-4 表达与治疗抵抗相关。通过组合使用 CTLA-4 免疫检查点阻断和 IFNα LV 递送来靶向调节性 T 细胞功能，可扩展肿瘤反应性 T 细胞，使大多数小鼠获得完全缓解。这些发现支持了一种有前途的治疗策略，具有转化为满足未满足医疗需求的患者的可行性。
