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体内巨噬细胞工程重塑肿瘤微环境来根除肝转移灶
2023-10-21 23:35
来源：小柯机器人

近日，意大利圣拉斐尔生命健康大学Mario Leonardo Squadrito等研究人员合作发现，体内巨噬细胞工程重塑肿瘤微环境来根除肝转移灶。该项研究成果于2023年10月19日在线发表在《癌细胞》杂志上。

研究人员描述了一种慢病毒载体（LV）平台，该平台可选择性地设计肝脏巨噬细胞，包括库普否细胞和肿瘤相关巨噬细胞（TAM），从而向肝转移灶输送I型干扰素（IFNα）。基于基因的IFNα递送可延缓小鼠结直肠癌和胰腺导管腺癌肝转移灶的生长。对IFNα的反应与TAM免疫激活、MHC-II限制性抗原递呈增强和CD8+ T细胞耗竭减少有关。
 
相反，IL-10信号的增加、Eomes CD4+ T细胞（一种显示I型调节性T细胞特征的细胞类型）的扩增以及CTLA-4的表达则与耐药性有关。通过CTLA-4免疫检查点阻断和IFNα LV递送组合来靶向调节性T细胞功能，可扩增肿瘤反应性T细胞，使大多数小鼠获得完全应答。这些研究结果支持了一种前景广阔的治疗策略，可应用于有医疗需求的患者。

据介绍，肝转移瘤对目前的药物治疗（包括免疫疗法）反应不佳。

附：英文原文

Title: In vivo macrophage engineering reshapes the tumor microenvironment leading to eradication of liver metastases

Author: Thomas Kerzel, Giovanna Giacca, Stefano Beretta, Chiara Bresesti, Marco Notaro, Giulia Maria Scotti, Chiara Balestrieri, Tamara Canu, Miriam Redegalli, Federica Pedica, Marco Genua, Renato Ostuni, Anna Kajaste-Rudnitski, Masanobu Oshima, Giovanni Tonon, Ivan Merelli, Luca Aldrighetti, Paolo Dellabona, Nadia Coltella, Claudio Doglioni, Paola M.V. Rancoita, Francesca Sanvito, Luigi Naldini, Mario Leonardo Squadrito

Issue&Volume: 2023-10-19

Abstract: 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.

DOI: 10.1016/j.ccell.2023.09.014

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00347-1

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
官方网址：https://www.cell.com/cancer-cell/home
投稿链接：https://www.editorialmanager.com/cancer-cell/default.aspx


本期文章：《癌细胞》：Online/在线发表

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